Genetics News

1790 G/A polymorphism, but not 1772 C/T polymorphism, is significantly associated with Cancers: An update study

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Jie Liu , Hong-xin Zhang

This study aimed to investigate the association between PASD8 gene and cancers. For 1772 C/T polymorphism (rs11549465), it included 5552 cases and 8044 controls, and for 1790 G/A (rs11549467), 3381 cases and 5830 controls. The allele-analysis results showed that 1772 C/T (rs11549465) was significantly associated with cancers (OR: 1.177, 95% CI: 1.011–1.369, p=0.035). And results of genotype-analysis indicated that 1790 G/A (rs11549467) had a significant relationship with cancers. (OR: 0.736, 95% CI: 0.595–0.910, p=0.005). For 1790 G/A (rs11549467), the association was significant when subdivided by different kinds of cancers. And no association existed when subdivided into population-type subgroups. In conclusion, PASD8 gene played an important role in the development of cancers.

6p21.2–p12.3 deletion detected by aCGH in an 8-year-old girl with cleidocranial dysplasia and developmental delay

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Chih-Ping Chen , Shuan-Pei Lin , Yu-Peng Liu , Schu-Rern Chern , Peih-Shan Wu , Yu-Ting Chen , Jun-Wei Su , Chen-Chi Lee , Wayseen Wang

We present an 8-year-old girl with cleidocranial dysplasia, psychomotor developmental delay, poor wound healing and a 6p21.2–p12.3 deletion detected by aCGH. The patient was previously found to have a normal karyotype on conventional cytogenetic analysis and no RUNX2 mutation on sequence analysis. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of CUL7, VEGFA, NFKBIE and RUNX2 in this case.

A novel COMP mutation in a Chinese patient with pseudoachondroplasia

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Xuemei Xie , Lihong Liao , Jinzhi Gao , Xiaoping Luo

A 2.75-year-old Chinese boy presented with typical clinical features of pseudoachondroplasia, including disproportionate short-limb short stature, brachydactyly, genu varus and waddling gait. Radiologically, tubular bones were short with widened metaphyses, irregular and small epiphyses; anterior tonguing or beaking of vertebral bodies were characteristic. DNA sequencing analysis of the COMP gene revealed a heterozygous mutation (c.1511G>A, p.Cys504Tyr) in the patient but his parents were unaffected without this genetic change. The missense mutation (c.1511G>A) was not found in 100 healthy controls and has not been reported previously. Our findings expand the spectrum of known mutations in COMP leading to pseudoachondroplasia.

ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Yan-Fang Niu , Wang Ni , Zhi-Ying Wu

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder resulting from mutations within the ABCD1 gene. Adrenomyeloneuropathy (AMN) and childhood cerebral ALD (CCALD) are most common phenotypes in the Western ALD patients. Here we performed mutation analysis of ABCD1 in 10 Chinese ALD families and identified 8 mutations, including one novel deletion (c.1477_1488+11del23) and 7 known mutations. Mutations c.1772G>A and c.1816T>C were first reported in the Chinese patients. Mutations c.1661G>A and c.1679C>T were demonstrated to be de novo mutations. The dinucleotide deletion 1415_16delAG, described as a mutational hotspot in different ethnic groups, was identified in two families. In addition, we performed a retrospective nation-wide mutation study of X-linked ALD in China based on a literature review. The retrospective study further confirmed the hypothesis that exon 6 is a potential mutation cluster region in the Asian populations. Furthermore, it suggested that CCALD is the most common phenotype in China.

Analysis of CLDN14 gene in deaf Moroccan patients with non-syndromic hearing loss

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Majida Charif , Amina Bakhchane , Omar Abidi , Redouane Boulouiz , Abdelmajid Eloualid , Rachida Roky , Hassan Rouba , Mostafa Kandil , Guy Lenaers , Abdelhamid Barakat

Mutations in the CLDN14 gene, encoding the tight junction claudin 14 protein has been reported to date in an autosomal recessive form of isolated hearing loss DFNB29. In order to identify the contribution of CLDN14 to inherited deafness in Moroccan population, we performed a genetic analysis of this gene in 80 Moroccan familial cases. Our results show the presence of 7 mutations: 6 being conservative and one leading to a missense mutation (C11T) which was found at heterozygous and homozygous states, with a general frequency of 6.87%. The pathogenicity of the resulting T4M substitution is under discussion.

Finally, our study suggests that CLDN14 gene can be implicated in the development of hearing loss in the Moroccan population.

Analysis of new Matrilin-1 gene variants in a case–control study related to dental malocclusions in Equus asinus

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): João B. Rodrigues , Stéphane Araújo , Henrique Guedes-Pinto , Fidel San Roman , Carlos Viegas , Estela Bastos

Prognathism and brachygnathism are craniofacial deformities that severely affect the health of human and vertebrates, such as donkeys. The multifactorial etiology of this disease makes the genetic analysis a powerful tool for its understanding and prevention of spreading these deformities.

This study aims to contribute to the characterization of the genetic basis of prognathism and brachygnathism in donkeys, using the Zamorano-Leonés donkey, an endangered Spanish breed, as a model. Matrilin-1 (MATN1) polymorphisms have been previously described as markers for mandibular prognathism in Korean and Japanese human populations. Genetic variations in MATN1 gene were sought, in order to verify its association in a case–control study, including 30 donkeys presenting brachygnathism, 30 donkeys presenting prognathism and 30 donkeys with normal occlusion phenotypes. One genetic variation (g503G>A) located in an intronic region of MATN1 gene was identified and characterized. Statistically significant differences were detected between the control group and prognathism cases, but no statistical significant results were found between the control group and the brachygnathism cases. These results support evidence for an important role of MATN1 on prognathism in the analyzed population with MATN1 genetic variation – 503G>A – having a protective effect. Further studies should be developed in order to understand the whole role of MATN1 and the mechanisms affected by its genetic variations.

Apolipoprotein E gene polymorphisms in Lebanese with hypercholesterolemia

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Rami A. Mahfouz , Khalil M. Charafeddine , Rita F. Tanios , Nathalie M. Karaky , Rabab N. Abdul Khalik , Rose T. Daher

Apolipoprotein E (ApoE) has an important role in the metabolism of lipids through its major isoforms (ε2, ε3, ε4). In particular, ApoE ε4, has been considered as a major genetic risk factor for cardiovascular diseases (CVD). The aim of our study is to investigate the frequency of ApoE gene polymorphisms (rs 429358C>T, rs 7412C>T) and their relationship to lipid parameters in a group of Lebanese hypercholesterolemic subjects (22 males and 24 females, aged 25–80years). Lipid profile, apolipoproteins A-I and B were determined using fasting serum samples; and molecular analysis of ApoE polymorphisms using blood in EDTA tubes. The distribution of the four ApoE genotypes detected in this study was: ε3/ε3 (73.9%), ε3/ε4 (17.4%), ε2/ε3 (6.5%), and ε2/ε4 (2.2%) resulting in allelic frequencies for ε2, ε3 and ε4 of 4.3%, 85.9% and 9.8%, respectively. No association was determined among any of the lipid parameters, gender and ApoE genotypes. Lipid parameters were not statistically different among various ApoE genotypes (p>0.05). ApoE ε2 frequency was found to be lower than that previously reported for healthy Lebanese (7.2%). CVD is one of the major leading causes of mortality in Lebanon with a reported prevalence of 12.2% in males and 7.7% in females, which incidentally agrees with our finding regarding ε4 allelic frequency of 13.6% in males and 6.3% in females. Consequently, larger prospective studies are recommended to highlight the correlation of ApoE polymorphisms to other biochemical and environmental factors involved in CVD.

Association between miR-146a rs2910164 polymorphism and autoimmune diseases susceptibility: A meta-analysis

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Hui Fang Chen , Ting Ting Hu , Xue Yan Zheng , Mei Qing Li , Min Hong Luo , Yue Xian Yao , Qing Chen , Shou Yi Yu

Published data on the rs2910164 in microRNA-146a (miR-146a) are shown to be associated with increased or decreased autoimmune diseases risk. To derive a more precise estimation of the relationship, we performed a meta-analysis to systematically summarize the possible. A meta-analysis including 11 studies with 3042 controls and 2197 cases was performed for genotypes CC (recessive effect), CC+CG (dominant effect) and C allele in fixed or random-effects models based on between-study heterogeneity. Overall, no significant association between miR-146a G/C rs2910164 polymorphism and autoimmune diseases risk was found in all genetic models when all studies were pooled into the meta-analysis. SLE (OR=0.99, 95% CI: 0.90–1.10), RA (OR=0.98, 95% CI: 0.85–1.14) did not yield statistical significance as for C allele pooled studies. In the subgroup analysis by ethnicity, still no significant association was detected in all genetic models. Our meta-analysis suggests that there is no association between miR-146a G/C rs2910164 polymorphism and the development of autoimmune diseases.

Association between the XRCC3 T241M polymorphism and risk of cancer: Evidence from 157 case–control studies

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Xiao-Feng He , Wu Wei , Jia-Lin Li , Xu-Liang Shen , Da-peng Ding , Su-Lan Wang , Zhi-Zhong Liu , Jiang-Bo Qin , Li-Xia Wu , Dao-Lin Xie

The T241M polymorphism in the X-ray cross-complementing group 3 (XRCC3) had been implicated in cancer susceptibility. The previous published data on the association between XRCC3 T241M polymorphism and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and XRCC3 T241M (61,861 cases and 84,584 controls from 157 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR]=1.07, 95% confidence interval [CI]=1.00–1.13; recessive model: OR=1.15, 95% CI=1.08–1.23; additive model: OR=1.17, 95% CI=1.08–1.28) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of bladder cancer and breast cancer, especially in Caucasians. In addition, significantly decreased lung cancer risk was also observed. In summary, this meta-analysis suggests the participation of XRCC3 T241M in the susceptibility for bladder cancer and breast cancer, especially in Caucasians, and XRCC3 T241M polymorphism is associated with decreased lung cancer risk. Moreover, our work also points out the importance of new studies for T241M association in some cancer types, such as gastric cancer, colorectal cancer, and melanoma skin cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC3 polymorphism in cancer development.

Association of interleukin-13 SNP rs20541 with allergic rhinitis risk: A meta-analysis

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Xin-Jiang Ying , Shu-Wei Zhao , Guo-Liang Wang , Jin Xie , Hong-Ming Xu , Pin Dong

Studies investigating the association between interleukin-13 (IL-13) single nucleotide polymorphism (SNP) rs20541 and allergic rhinitis (AR) risk have reported conflicting results. The aim of the present study was to conduct a meta-analysis assessing the possible association of IL-13 SNP rs20541 with AR risk. Eight studies were included in the present meta-analysis (2153 cases and 3931 controls). The combined results based on all studies showed that IL-13 SNP rs20541 was associated with increased AR risk (Gln versus Arg: odds ratio (OR)=1.18, 95% confidence interval (CI)=1.08–1.30; Gln/Gln versus Arg/Arg: OR=1.52, 95% CI=1.20–1.92; Arg/Gln+Gln/Gln versus Arg/Arg: OR=1.19, 95% CI=1.06–1.33; Gln/Gln versus Arg/Gln+Arg/Arg: OR=1.42, 95% CI=1.13–1.79). When stratifying for race, IL-13 SNP rs20541 exhibited increased AR risk in Asians (Gln versus Arg: OR=1.20, 95% CI=1.06–1.36; Gln/Gln versus Arg/Arg: OR=1.57, 95% CI=1.17–2.12; Arg/Gln+Gln/Gln versus Arg/Arg: OR=1.22, 95% CI=1.04–1.44; Gln/Gln versus Arg/Gln+Arg/Arg: OR=1.45, 95% CI=1.09–1.93), while no significant association was detected in Caucasians (Gln versus Arg: OR=1.28, 95% CI=0.93~1.78; Gln/Gln versus Arg/Arg: OR=1.42, 95% CI=0.96–2.11; Arg/Gln+Gln/Gln versus Arg/Arg: OR=1.35, 95% CI=0.89–2.05; Gln/Gln versus Arg/Gln+Arg/Arg: OR=1.37, 95% CI=0.93–2.02). This meta-analysis supported that IL-13 SNP rs20541 was associated with AR, particularly in Asians.

Association of the interleukin-10 −592A/C, −1082G/A and −819T/C gene polymorphisms with type 2 diabetes: A meta-analysis

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Jing Li , Song Wu , Ming-Rui Wang , Ting-Ting Wang , Ji-Min Zhu

There is more evidence that interleukin-10 (IL-10), as a multifunctional regulatory cytokine of inflammatory responses, may have an important role in type 2 diabetes (T2D). However, genetic association studies that evaluated the relationship between IL-10 gene variants and T2D have produced conflicting results. The aim of this study was to determine whether the IL-10 gene polymorphisms (−592A/C, −1082G/A, −819T/C) conferred susceptibility to T2D through a meta-analysis. A comprehensive search was conducted to examine all the eligible studies. A total of 9 studies involving 2838 T2D patients and 2773 controls were considered in the meta-analysis. Overall, there was no significant association between IL-10 −592A/C and T2D (A vs C: OR =0.93, P =0.625; AA+AC vs CC: OR =0.89, P =0.511; AA vs AC+CC: OR =0.93, P =0.821). We failed to find the association between the IL-10 −1082G allele and T2D (OR =1.04, P =0.430), but the genotypes of the IL-10 −1082G/A polymorphism conferred a risk for the development of T2D (GA vs AA: OR =1.21, P =0.027; GG+GA vs AA: OR =1.17, P =0.048). Analysis of the −819T/C polymorphism revealed no significant association with T2D (T vs C: OR =1.04, P =0.853; TT+TC vs CC: OR =1.07, P =0.834; TT vs TC+CC: OR =1.08, P =0.824). In conclusion, the present meta-analysis suggests association between the IL-10 −1082G/A polymorphism and T2D. However, additional well-designed and larger scale primary studies are required to further evaluate the IL-10 gene polymorphisms and T2D.

Case scenario and inquiry in response to: Diagnostic utility of HFE variants in Spanish patients. Gene 2013; 514 (1): 31–35

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Michael A. Hansen , Meenakshi B. Bhattacharjee , Modushudan Bhattacharjee

CC chemokine receptor-3 as new target for age-related macular degeneration

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Neel Kamal Sharma , Amod Gupta , Sudesh Prabhakar , Ramandeep Singh , Arvind Kumar Bhatt , Akshay Anand

CC chemokine receptor-3 (CCR3) is involved in angiogenic processes. Recently, CCR3 was accounted to participate in choroidal neovascularization (CNV) and CCR3 targeting was reported to be superior to standard antivascular endothelial growth factor-A (VEGF-A) administration when tested in an artificially induced CNV in animals. As human CCR3 studies are lacking in age-related macular degeneration (AMD) patients we sought to determine if CCR3 has any association with inflammatory processes that occur in CNV. A total of 176 subjects were included on the basis of inclusion criteria. Real time PCR was used to analyze the single nucleotide polymorphism in CCR3 of AMD (115) and normal controls (n=61). Genotype frequency was adjusted for possible confounders like cigarette smoking, alcohol, meat consumption and other risk factors. Chi-square test was used for analysis of polymorphism. The genotype distribution of CCR3 (rs3091250) polymorphism was significantly different in AMD patients in the Indian population. GT (heterozygous) and TT (homozygous) at the rs3091250 SNP increased risk of AMD as compared to the GG genotypes (OR=4.8, CI 95%=2.2–10.8 and OR=4.1, CI 95%=1.6–10.1 respectively). Subgroup analysis of AMD patients in wet and dry revealed no significant differences. There was no significant difference for rs3091312 in AMD and control group. A significant association between AMD and CCR3 (rs3091250) polymorphism localized on chromosome 3p21.3 was detected. The results suggest the possible contribution of rs3091250, a new predisposing allele in AMD.

Cellular overexpression of Aquaporins slows down the natural HIF-2α degradation during prolonged hypoxia

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Ana Galán-Cobo , Rocío Sánchez-Silva , Ana Serna , Irene Abreu-Rodríguez , Ana María Muñoz-Cabello , Miriam Echevarría

Overexpression of cell membrane aquaporins (AQPs) has recently been associated with tumor formation, particularly with angiogenesis, cell migration and proliferation. Additionally, the hypoxia inducible factor (HIF) family has been extensively implicated in tumor growth and recent studies evidence interplay between AQP expression and HIF stability. Therefore, we decided to explore the effect that AQP overexpression has on the long-term stability of HIF-2α in PC12 cells exposed to chronic hypoxia, characteristic of a growing tumor. HIF-2α levels were analyzed in five PC12 clones with stable overexpression of different proteins (AQP1, AQP3, AQP5, G6PD, and GDNF), in PC12 transiently expressing G6PD or Kv4.2, and in wild-type PC12 cells. Overexpression of AQP1, 3 or 5 in PC12 cells (o-AQP-c) prevented the HIF-2α down-expression otherwise observed, after 16h at 1% O2, in wt-PC12 and in PC12 overexpressing non-AQP proteins. Longer HIF-2α stability was also observed in o-AQP-c exposed to cobalt chloride or dimethyloxallyl glycine. Normal proteasome activity was confirmed in all clones analyzed. Levels of HIF target genes (PHD2 and 3, VEGF, and PGK1) were 2–4 fold higher in hypoxic o-AQP-c than in wt-PC12 cells, and morphological changes in colony shape together with higher cell proliferation rates were observed in all o-AQP-c. Interestingly, analysis of PHD levels under normoxia revealed lower (50%) PHD3 expression in o-AQP-c than in controls. Our results indicate that AQP overexpression in PC12 cells prolongs HIF-2α stability during chronic hypoxia, leading to higher level of induction of its target genes and likely conferring to these cells a more tumor-like phenotype.

Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly, mental retardation and leukencephalopathy

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Sylvie Nguyen-Minh , Katrin Drossel , Denise Horn , Imma Rost , Birgit Spors , Angela M. Kaindl

Chromosome 18 abnormalities rank among the most common autosomal anomalies with 18q being the most frequently affected. A deletion of 18q has been attributed to microcephaly, mental retardation, short stature, facial dysmorphism, myelination disorders, limb and genitourinary malformations and congenital aural atresia. On the other hand, duplications of 18q have been associated with the phenotype of Edwards syndrome. Critical chromosomal regions for both phenotypes are contentious. In this report, we describe the first case of an 11-year old male with a combined interstitial duplication 18q22.1, triplication 18q22.1q22.2 and terminal deletion 18q22.2q23 with phenotypic features of isolated 18q deletion syndrome and absence of phenotypic features characteristic of Edwards syndrome despite duplication of the suggested critical region. This report allows for reevaluation of proposed critical intervals for the phenotypes in deletion 18q syndrome and Edwards syndrome.

Comment on: ‘Interleukin-28 polymorphisms on the SVR in the treatment of naïve chronic hepatitis C with pegylated interferon-α plus ribavirin: A meta-analysis’

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Amanda Fernández-Rodríguez , María Ángeles Jiménez-Sousa , Salvador Resino

Comparative analysis of cation/proton antiporter superfamily in plants

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Chu-Yu Ye , Xiaohan Yang , Xinli Xia , Weilun Yin

The cation/proton antiporter superfamily is associated with the transport of monovalent cations across membranes. This superfamily was annotated in the Arabidopsis genome and some members were functionally characterized. In the present study, a systematic analysis of the cation/proton antiporter genes in diverse plant species was reported. We identified 240 cation/proton antiporters in alga, moss, and angiosperm. A phylogenetic tree was constructed showing these 240 members are separated into three families, i.e., Na⁺/H⁺ exchangers, K⁺ efflux antiporters, and cation/H⁺ exchangers. Our analysis revealed that tandem and/or segmental duplications contribute to the expansion of cation/H⁺ exchangers in the examined angiosperm species. Sliding window analysis of the nonsynonymous/synonymous substitution ratios showed some differences in the evolutionary fate of cation/proton antiporter paralogs. Furthermore, we identified over-represented motifs among these 240 proteins and found most motifs are family specific, demonstrating diverse evolution of the cation/proton antiporters among three families. In addition, we investigated the co-expressed genes of the cation/proton antiporters in Arabidopsis thaliana. The results showed some biological processes are enriched in the co-expressed genes, suggesting the cation/proton antiporters may be involved in these biological processes. Taken together, this study furthers our knowledge on cation/proton antiporters in plants.

Corrigendum to “Molecular cloning and characterization of the anti-obesity gene adipose in pig” [GENE 509 (2012) 110–119]

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Yanling Wu , Qinqiang Long , Bin Feng , Xiaoyue Zhu , Zifeng Zheng , Sumin Gao , Mingju Gao , Li Gan , Lei Zhou , Zaiqing Yang

Different effects of PPARA, PPARG and ApoE SNPs on serum lipids in patients with coronary heart disease based on the presence of diabetes

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Hulya Yilmaz-Aydogan , Ozlem Kurnaz , Ozlem Kucukhuseyin , Basak Akadam-Teker , Ozlem Kurt , Allison Pinar Eronat , Atike Tekeli , Zehra Bugra , Oguz Ozturk

Background

The aim of this study was to investigate the individual or combined effects of PPARA-L162V, PPARG-C161T and APOE polymorphisms on hyperlipidemia in coronary heart disease (CHD) patients.

Methods

Our study included 223 patients with CHD (103 with type 2 diabetes (T2DM), 120 without diabetes) and 101 controls. All genotypes were determined by PCR–RFLP technique.

Results

Genotypic and allelic distributions of PPARA-L162V polymorphism were similar between study and control groups (p >0.05). The serum total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels were higher in PPARA-V162 allele carriers in non-diabetic CHD patients (p =0.007 and p =0.038, respectively). The increasing effect of the PPARA-V162 allele on serum TC and LDL-C levels was weakened with the presence of PPARG-161T allele in the non-diabetic CHD patients. The ApoE4–PPARA-V162 allelic combination of the ApoE/PPARA genes was found to be more frequent in diabetic CHD patients independent of serum lipids (p =0.035).

Conclusions

The PPARA V162 allele has an increasing effect on TC and LDL-C levels and this effect was reduced by carrying PPARG T161 allele in non-diabetic CHD patients. On the other hand, the V162 allele may be associated with an increased risk of CHD in diabetic CHD patients due to the presence of ApoE4 allele independent of serum lipids. We suggest that the PPARA L162V polymorphism may have diverse effects on serum lipids and CHD risk depends on the presence of T2DM.

Editorial Board

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Evidence of colorectal cancer risk associated variant Lys25Ser in the proximity of human bone morphogenetic protein 2

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Wajahatullah Khan , Zainularifeen Abduljaleel , Mohammed Alanazi , Mohamed Elrobh

Colorectal cancer (CRC) is the third most prevalent cancer and fourth leading cause of cancer-related deaths globally. It has been shown that the nsSNP variants play an important role in diseases, however it remained unclear how these variants are associated with the disease. Recently, several CRC risk associated SNPs have been discovered, however rs961253 (Lys25Arg at 20p12.3) located in the proximity of bone morphogenetic protein 2 (Bmp2) and fermitin family homolog 1 Fermt1 genes have been reported to be highly associated with the CRC risk. Here we provide evidence for the first time in silico biological functional and structural implications of non-synonymous (nsSNPs) CRC disease-associated variant Lys25Arg via molecular dynamic (MD) simulation. Protein structural analysis was performed with a particular variant allele (A/C, Lys25Arg) and compared with the predicted native protein structure. Our results showed that this nsSNP will cause changes in the protein structure and as a result is associated with the disease. In addition to the native and mutant 3D structures of CRC associated risk allele protein domain (CRAPD), they were also analyzed using solvent accessibility models for further protein stability confirmation. Taken together, this study confirmed that this variant has functional effect and structural impact on the CRAPD and may play an important role in CRC disease progression; hence it could be a reasonable approach for studying the effect of other deleterious variants in future studies.

Familial porphyria cutanea tarda in Spain: Characterization of eight novel mutations in the UROD gene and haplotype analysis of the common p.G281E mutation

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Sara Gómez-Abecia , María-Josefa Morán-Jiménez , Eva Ruiz-Casares , Nuno Henriques-Gil , Inmaculada García-Pastor , María-Concepción Garrido-Astray , Rafael Enríquez de Salamanca , Manuel Méndez

Porphyria cutanea tarda (PCT) results from decreased activity of uroporphyrinogen decarboxylase (UROD) in the liver. Deficiency in this enzyme results in accumulation of highly carboxylated porphyrins responsible for the disease. PCT usually occurs in adulthood and is characterized by cutaneous photosensitivity, hyperpigmentation, skin fragility and hypertrichosis. Familial PCT (F-PCT) occurs in 20–30% of patients in whom UROD gene mutations in heterozygosity decrease the enzymatic activity to about 50% in all tissues. The rare homozygous form of F-PCT (hepatoerythropoietic porphyria) has more severe clinical features and onset in childhood. In Spain, F-PCT is molecularly heterogeneous and the most frequent UROD mutation is p.G281E. In the present study, we searched for the molecular defect causing F-PCT in a group of Spanish patients and investigated whether the p.G281E mutation in the Spanish population came from a single or various origins. Among seventeen F-PCT patients, sixteen UROD mutations were identified, including eight novel ones: six missense (p.A23V, p.L78P, p.W180G, p.T196I, p.E278G and p.V279M), one frameshift (c.233delT) and one splice site mutation (c.774G>C). Prokaryotic expression studies showed the detrimental effect for each missense mutation, whereas reverse transcription-PCR and sequencing demonstrated that the novel splice site mutation caused exon 7 skipping. Moreover, haplotype analysis performed in Spanish families with the p.G281E mutation indicated that this lesion is associated with at least five haplotype backgrounds. These results extend knowledge on the molecular heterogeneity of F-PCT and suggest multiple origins of the p.G281E mutation.

Further evidence for the contribution of the vascular endothelial growth factor gene in coronary artery disease susceptibility

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Q.T. Cui , Y. Li , C.H. Duan , W. Zhang , X.L. Guo

Coronary artery disease (CAD) receives intensive attentions in the research of cardiovascular diseases, due to its high incidence and severe impact on the quality of life vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, has been strongly implicated in the pathogenesis of CAD. Genetic markers in different regions of the VEGF gene have a plausible role in modulating the risk of CAD. To identify the markers contributing to the genetic susceptibility to CAD, we examined the potential association between CAD and 10 single nucleotide polymorphisms (SNPs, rs699947, rs1570360, rs2010963, rs833068, rs3024997, rs3025000, rs3025010, rs3025020, rs3025030, rs3025039) of the VEGF gene using the MassARRAY system. Participants included 242 CAD patients and 253 healthy controls from a Chinese Han Population (He'nan Province, China). The allelic or genotypic frequencies of the rs699947 (5′ untranslated regions, 5′UTR) and rs2010963 (5′UTR) polymorphisms in the CAD patients were significantly different from those in the healthy controls. The CAD patients had significantly higher frequency of the rs699947 A allele (χ² =11.141, P =0.001, OR=1.665, 95% CI=1.232–2.250) and rs2010963 C allele (χ² =13.593, P =0.0002, OR=1.611, 95% CI=1.249–2.077). Strong linkage disequilibrium was observed in the rs699947–rs1570360–rs2010963 haplotype block (D’>0.9). Significantly more C–G–C haplotypes (P =0.040) and significantly fewer C–G–G haplotypes (P =0.0004) were found in the CAD patients. The possible association of rs699947 and rs2010963 with CAD risks warrant confirmation in independent case–control studies and may be informative for future investigations on the pathogenesis of CAD.

Genetic analysis of auditory neuropathy spectrum disorder in the Korean population

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Seung-Hyun Bae , Jeong-In Baek , Jong Dae Lee , Mee Hyun Song , Tae-Jun Kwon , Se-Kyung Oh , Ji Yun Jeong , Jae Young Choi , Kyu-Yup Lee , Un-Kyung Kim

Auditory neuropathy spectrum disorder (ANSD) is caused by dys-synchronous auditory neural response as a result of impairment of the functions of the auditory nerve or inner hair cells, or synapses between inner hair cells and the auditory nerve. To identify a causative gene causing ANSD in the Korean population, we conducted gene screening of the OTOF, DIAPH3, and PJVK genes in 19 unrelated Korean patients with ANSD. A novel nonsense mutation (p.Y1064X) and a known pathogenic mutation (p.R1939Q) of the OTOF gene were identified in a patient as compound heterozygote. Pedigree analysis for these mutations showed co-segregation of mutation genotype and the disease in the family, and it supported that the p.Y1064X might be a novel genetic cause of autosomal recessive ANSD. A novel missense variant p.K1017R (c.3050A>G) in the DIAPH3 gene was also identified in the heterozygous state. In contrast, no mutation was detected in the PJVK gene. These results indicate that no major causative gene has been reported to date in the Korean population and that pathogenic mutations in undiscovered candidate genes may have an effect on ANSD.

Genetic variation in exon 10 of the BPI gene is associated with Escherichia coli F18 susceptibility in Sutai piglets

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Lu Liu , Jing Wang , Qiaohui Zhao , Chen Zi , Zhengchang Wu , Xianmin Su , Yongjiu Huo , Guoqiang Zhu , Shenglong Wu , Wenbin Bao

Our aim was to investigate the effect of the porcine bactericidal/permeability-increasing protein (BPI) on the susceptibility to enterotoxigenic Escherichia coli F18 (ETEC F18). Specifically, we wanted to determine whether the HpaII restriction polymorphism in exon 10 of BPI mediates susceptibility to ETEC F18. Thirty verified ETEC F18-resistant and thirty susceptible Sutai (Duroc×Taihu) piglets were identified using the receptor binding assay. Exon 10 of the BPI gene produced the AA, BB, and AB genotypes after HpaII digestion. The genotype distribution among ETEC F18-resistant piglets was significantly different from that among susceptible piglets. Among piglets with the AA genotype, 90% were ETEC F18-resistant; this percentage of resistant piglets was significantly higher than the percentage of resistant piglets with the AB (57.1%) and BB genotypes (17.4%). There was high expression only in the tissues of the duodenum and jejunum, wherein the expression levels in the ETEC F18-resistant group were significantly higher than those in the susceptible group (P <0.05). The average expression levels in individuals with the AA genotype were significantly higher than those in individuals with the AB or BB genotype (P <0.05), while the results of Western blot show the same evidences as real time PCR. These results indicate that the upregulation of porcine BPI gene expression in the small intestines plays a direct role in resistance to ETEC F18 infection. The AA genotype for the HpaII site in exon 10 of the porcine BPI gene was demonstrated to be an anti-ETEC F18 marker and could be used for selective breeding to enhance ETEC F18 resistance.

GSTM1, GSTT1, GSTP1, and GSTA1 genetic variants are not associated with coronary artery disease in Taiwan

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Hseng-Long Yeh , Li-Tang Kuo , Fung-Chang Sung , Cheng-Wen Chiang , Chih-Ching Yeh

Background and objective

The genetic variants of xenobiotic-metabolizing enzymes, such as those encoded by glutathione-S-transferase (GST) genes, may be associated with the risk of coronary artery disease (CAD). To investigate the genetic factors for CAD, we examined the GSTM1, GSTT1, GSTP1, and GSTA1 genotypes in a CAD cohort in Taiwan.

Methods

Our study included 458 CAD participants and 209 control participants who received coronary angiography to assess CAD. The severity of CAD was defined as the number of coronary vessels with 50% or greater stenosis. Sequence variation of the GSTM1 and GSTT1 genes was determined using a polymerase chain reaction (PCR). The GSTP1 (Ile105Val), and GSTA1 (-69C>T) genetic variants were identified using a combination of PCR and restriction fragment length polymorphism analysis. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals.

Results

Among the GST genetic variants examined, the GSTT1 null genotype was more prevalent in CAD participants with 3 stenosed vessels than in control participants (OR=1.64, P =.02). This association was no longer observed after adjusting for age, sex, smoking, alcohol use, diabetes mellitus, and serum levels of total cholesterol and high-density lipoprotein cholesterol (OR=1.28, P =.40). Both univariate and multivariate logistic regression analyses found no significant associations between CAD and the other genetic variants, either separately or in combination. In addition, no effects of interactions between the genotypes and environmental factors, such as cigarette smoking, were significantly associated with the risk of CAD.

Conclusion

The GST genetic variants examined were not associated with susceptibility to CAD in our Taiwanese cohort. This null association requires further confirmation with larger samples.

Identification of one novel mutation in the C-propeptide of COL2A1 in a Chinese family with spondyloperipheral dysplasia

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Zeng Zhang , Shi-Chang Zhao , Jin-Wei He , Wen-Zhen Fu , Chang-Qing Zhang , Zhen-Lin Zhang

Spondyloperipheral dysplasia (SPD; OMIM 271700) is an autosomal dominant connective tissue disorder characterized by vertebral body abnormalities (platyspondyly, end-plate indentations), hip dysplasia and brachydactyly type E. Here, we identified a novel truncating mutation (p.Lys1444AsnfsX27) in the C-propeptide of type II collagen in an affected Chinese individual with SPD. Our findings will provide clues to the phenotype–genotype relations and may assist not only in the clinical diagnosis of SPD but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling.

Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Carolina P. Bellusci , Carlos Rocco , Paula Aulicino , Debora Mecikovsky , Verónica Curras , Soledad Hegoburu , Guillermo F. Bramuglia , Rosa Bologna , Luisa Sen , Andrea Mangano

Background

Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children.

Methods

Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2h after (Cpost-dose) the administration of the next dose of drug. CD4⁺ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r.

Results

MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose =3.04μg/ml and 6.50μg/ml, respectively; p =0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes=−0.50log10 copies/ml and −2.08log10 copies/ml, respectively; p =0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR.

Conclusions

Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4⁺ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.

Interleukin-18 gene polymorphisms and rheumatoid arthritis: A meta-analysis

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Jong Dae Ji , Won Jin Lee

Interleukin-18 (IL-18) is a member of the IL-1 superfamily that enhances both innate and acquired immune responses. IL-18 is highly expressed in sera, synovial fluids and synovial tissues of patients with RA, and these IL-18 levels are correlated with RA disease activity, indicating an important role of IL-18 in the pathogenesis of RA. Several studies have examined the association of IL-18 gene polymorphisms with RA, but these studies have shown inconclusive and controversial results. To verify the association between IL-18 gene polymorphism and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before October 2012. A meta-analysis on the association between the IL-18 rs1946518 SNP and RA was performed for 2944 patients with RA and 2377 controls from 7 published studies and a meta-analysis on the association between the IL-18 rs187238 SNP and RA was performed for 1319 patients with RA and 1211 controls from 5 published studies. In addition, 2 studies involving 1873 RA patients and 1092 controls were considered in the meta-analysis of the association between the IL-18 rs360722 SNP and RA. No significant association was found between two IL-18 SNPs (rs1946518 and rs187238) and RA susceptibility in all subjects. In subgroup analysis stratified by ethnicity, there was still no significant association between these two IL-18 SNPs and RA susceptibility. However, the frequency of the T allele at rs360722 was found to be significantly lower in patients with RA compared with controls, although this finding was based on only 2 studies. The results of our meta-analysis suggest that IL-18 rs360722 SNP is only associated with RA susceptibility. However, due to only two studies included in our meta-analysis, large-scale well designed studies should be considered in future studies to confirm the exact role of IL-18 rs360722 SNP in RA susceptibility.

Molecular cloning and expression analysis of estrogen receptor betas (ERβ1 and ERβ2) during gonad development in the Korean rockfish, Sebastes schlegeli

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): W.J. Mu , H.S. Wen , D. Shi , Y.P. Yang

Estrogen receptors (ER) play a crucial role in mediation of estrogen activities. Here we report the isolation and expression analysis of ERβ1 and ERβ2 from ovary Korean rockfish (Sebastes schlegeli). were isolated using reverse transcription-polymerase chain reaction (PCR) and rapid amplification of cDNA ends procedures. The cDNA of this study, ERβ1 (588 amino acids) and ERβ2 (659 amino acids) were identified using reverse-transcriptase PCR (RT-PCR) and rapid amplification of cDNA ends procedures. Structural analysis showed both ERβs contain six typical nuclear receptor-characteristic domains. Phylogenetic analysis indicated that Korean rockfish ERβs were highly conserved among teleost. RT-PCR confirmed that the ERβs were widely distributed in both gonads and extra gonadal tissues. Further, we analyzed the expression patterns of male and female S. schlegeli during the reproductive cycle using quantitative real-time PCR (qRT-PCR). The results showed that the highest expression levels were observed in testis at immature sperm stage for both of KrERβ1 and KrERβ2. For female, the expressions of KrERβ1 and KrERβ2 were significantly higher in the ovary at the early-oocyte stage. Cloning these two ERβ subtypes in the Korean rockfish, together with the information on expression levels in adult fish has given us the foundation to investigate their possible role in brain-pituitary-gonad neuroendocrine axis in future studies.

Molecular cloning of a plasma membrane Ca2+ ATPase (PMCA) from Y-organs of the blue crab (Callinectes sapidus), and determination of spatial and temporal patterns of PMCA gene expression

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Hsiang-Yin Chen , Robert D. Roer , R. Douglas Watson

Existing data indicate that a stage-specific increase in intracellular free Ca²⁺ stimulates ecdysteroid production by crustacean molting glands (Y-organs). The concentration of Ca²⁺ in cytosol is controlled mainly by proteins intrinsic to the plasma membrane and to the membranes of organelles. Several families of proteins are involved, including Ca²⁺ channels, Ca²⁺ pumps (ATPases), and Ca²⁺ exchangers. The family of Ca²⁺ pumps includes plasma membrane calcium ATPases (PMCAs). As a step toward understanding the involvement of calcium signaling in regulation of ecdysteroidogenesis, we used a PCR-based cloning strategy (RT-PCR followed by 3′- and 5′-RACE) to clone from Y-organs of the blue crab (Callinectes sapidus) a cDNA encoding a putative PMCA. The 4292base pair (bp) cDNA includes a 3510bp open reading frame encoding a 1170-residue protein (Cas-PMCA). The conceptually translated protein has a relative molecular mass of 128.8×10³ and contains all signature domains of an authentic PMCA, including ten transmembrane domains and a calmodulin binding site. The predicted membrane topography of Cas-PMCA is as expected for an authentic PMCA protein. A phylogenetic analysis of nonredundant amino acid sequences of PMCA proteins from different species showed Cas-PMCA clusters with other arthropod PMCA proteins. An assessment of tissue distribution showed the Cas-PMCA transcript to be broadly distributed in both neural and non-neural tissues. Studies using quantitative real-time PCR revealed stage-specific changes in Cas-PMCA abundance during the molting cycle, with peak expression occurring during premolt stage D2, a pattern consistent with the hypothesis that Cas-PMCA functions to maintain cellular Ca²⁺ homeostasis in Y-organs.

Molecular cloning, expression, and hormonal regulation of the chicken microsomal triglyceride transfer protein

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): N. Erwin Ivessa , Edward Rehberg , Bernadette Kienzle , Fridolin Seif , Robert Hermann , Marcela Hermann , Wolfgang J. Schneider , David A. Gordon

During an egg-laying cycle, oviparous animals transfer massive amounts of triglycerides, the major lipid component of very low density lipoprotein (VLDL), from the liver to the developing oocytes. A major stimulus for this process is the rise in estrogen associated with the onset of an egg-laying cycle. In mammals, the microsomal triglyceride transfer protein (MTP) is required for VLDL assembly and secretion. To enable studies to determine if MTP plays a role in basal and estrogen-stimulated VLDL assembly and secretion in an oviparous vertebrate, we have cloned and sequenced the chicken MTP cDNA. This cDNA encodes a protein of 893 amino acids with an N-terminal signal sequence. The primary sequence of chicken MTP is, on average, 65% identical to that of mammalian homologs, and 23% identical to the Drosophila melanogaster protein. We have obtained a clone of chicken embryo fibroblast cells that stably express the avian MTP cDNA and show that these cells display MTP activity as measured by the transfer of a fluorescently labeled neutral lipid. As in mammals, chicken MTP is localized to the endoplasmic reticulum as revealed by indirect immunofluorescence and by the fact that its N-linked oligosaccharide moiety remains sensitive to endoglycosidase H. Endogenous, enzymatically active MTP is also expressed in an estrogen receptor-expressing chicken hepatoma cell line that secretes apolipoprotein B-containing lipoproteins. In this cell line and in vivo, the expression and activity of MTP are not influenced by estrogen. Therefore, up-regulation of MTP in the liver is not required for the increased VLDL assembly during egg production in the chicken. This indicates that MTP is not rate-limiting, even for the massive estrogen-induced secretion of VLDL accompanying an egg-laying cycle.

New mutation in the myocilin gene segregates with juvenile-onset open-angle glaucoma in a Brazilian family

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Carolina Ayumi Braghini , Izabella Agostinho Pena Neshich , Goran Neshich , Fernanda Caroline Soardi , Maricilda Palandi de Mello , Vital Paulino Costa , José Paulo Cabral de Vasconcellos , Mônica Barbosa de Melo

Mutations in the myocilin gene (MYOC) account for most cases of autosomal dominant juvenile-onset open-angle glaucoma (JOAG), an earlier and more severe form of POAG. We accessed seven members of a Brazilian JOAG family by clinical and molecular investigation. Four out of seven family members were diagnosed with JOAG. All of these patients presented high intraocular pressure and two of them were bilaterally blind. The disease onset varied from 20 to 30years old. There was a nine-year-old family member who had not yet manifested the disease, although he was also a carrier of the mutation. Ophthalmologic examination included: evaluation of the visual field and optic disc, intraocular pressure measurement, and gonioscopy. The three exons and intron/exon junctions of the MYOC gene were screened for mutations through direct sequencing of PCR-amplified DNA fragments. Mutation screening revealed an in-frame mutation in the third exon of the MYOC gene: an insertion of six nucleotides between the cDNA positions 1187 and 1188 (c.1187_1188insCCCAGA, p.D395_E396insDP). This mutation presented an autosomal dominant pattern of inheritance, segregating with the disease in four family members for three generations, and it was absent in 60 normal controls. We also performed a computational structure modeling of olfactomedin-like domain of myocilin protein and conducted in silico analysis to predict the structural changes in the myocilin protein due to the presence of the mutation. These findings may be important for future diagnosis of other presymptomatic family members, as well as for the increase of the panel of MYOC mutations and their effects on phenotype.

Novel deletion mutation of TRPS1 gene in a Chinese patient of trichorhinophalangeal syndrome type I

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Xu Nan , Shan Dai , Chun-ting Li , Xue-rong Chen , Hong-shan Zhao , Feng-shan Zhang , Qing-hua Song

Tricho–rhino–phalangeal syndrome (TRPS) is a rare autosomal dominant disorder. Deletion or mutation of the TRPS1 gene leads to the tricho–rhino–phalangeal syndromes type I or type III. In this article, we describe a Chinese patient affected with type I TRPS and showing prominent pilar, rhinal and phalangeal abnormalities. Mutational screening and sequence analysis of TRPS1 gene revealed a previously unidentified four-base-pair deletion of nucleotides 1783–1786 (c.1783_1786delACTT). The mutation causes a frame shift after codon 593, introducing a premature stop codon after 637 residues in the gene sequence. This deletion is an unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that sparse hair and metacarpal defects of tricho–rhino–phalangeal syndromes in this patient are due to this TRPS1 mutation. And this data further supports the critical role of TRPS1 gene in hair and partial skeleton morphogenesis.

Occurrence and analysis of imperfect microsatellites in diverse potyvirus genomes

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Ch. Mashhood Alam , B. George , Ch. Sharfuddin , S.K. Jain , S. Chakraborty

Simple sequence repeats (SSRs) or microsatellites are known to exhibit ubiquitous across all kingdoms of life including viruses. However, imperfections in simple sequence repeats have been analyzed in genomes of human, Escherichia coli and Human Immunodeficiency virus. The assessment of compound microsatellites in plant viral genomes is yet to be studied. Potyviruses severely affect crop plant growth and reduce economic yield in diverse cropping systems worldwide. Hence, we analyze the nature and distribution of compound microsatellites present in complete genome of 45 potyvirus species. The results indicate that compound microsatellites accounted for about 0% to 15.15% of all microsatellites and have low complexity as compared to that of prokaryotic genomes. Overall, 14% of compound microsatellites were of similar motifs and such motif duplications were observed for CA, TA and AG repeats. Among all 45 potyvirus genomes analyzed, SSR couple (AG)-x-(AC) was found to be the most abundant one. Hence it is apparent that in contrast to eukaryotes, majority of compound microsatellites in potyviruses were composed of variant motifs. We also highlight the relative frequency of different classes of compound microsatellites as well as their patterns of distribution and correlate with biology of potyviruses. Further characterization of such variation is important for elucidating the origin, mutational processes, and structure of these widely used, but incompletely understood sequences.

Plasmodium falciparum DOZI, an RNA helicase interacts with eIF4E

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Mohammed Tarique , Moaz Ahmad , Abulaish Ansari , Renu Tuteja

DEAD box RNA helicases play crucial roles in RNA metabolism such as splicing, ribosome biogenesis, RNA transport, degradation and translation. DDX6/DOZI (development of zygote inhibited) is one of the well characterized member of the DEAD box family and is highly conserved from humans to malaria parasite. DDX6 is involved in a variety of biological processes, which include the sexual development of the protozoan parasite. In the present manuscript we report that P. falciparum DOZI (DDX6 homologue); PfDZ50 contains the characteristic DNA and RNA binding, nucleic acid-dependent ATPase and RNA unwinding activities. Enzymatic characterization of truncated derivatives of PfDZ50 such as PfDZ50T1 (domain 1) and PfDZ50T2 (domain 2) shows that none of them contains ATPase activity. Furthermore, we confirmed that PfDZ50 interacts with PfeIF4E mainly through domain 1. Using in vitro translation assays we show that PfDZ50 inhibits translation. With the same assays we further report that externally added PfeIF4E restores ~70% of translation. Using immunofluorescence assays we demonstrate that PfDZ50 is localized mainly in the cytoplasm in the asexual intraerythrocytic developmental stages of P. falciparum. The localization pattern further suggests that PfDZ50 appears typically in granular bodies throughout the cytoplasm. Thus these studies will advance our knowledge regarding the function of PfDZ50/DDX6 in general.

Graphical abstract

Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Xing-mei Zhang , Li Li , Jin-jie Xu , Na Wang , Wei-juan Liu , Xuan-hao Lin , Yu-cai Fu , Li-li Luo

To maintain the normal length of female reproductive life, the majority of primordial follicles must be maintained in a quiescent state for later use. In this study, we aimed to study the effects of rapamycin on primordial follicle development and investigate the role of mTOR and sirtuin signaling. Rats were treated every other day with an intraperitoneal injection of rapamycin (5mg/kg) or vehicle. After 10weeks of treatment, ovaries were harvested for hematoxylin and eosin (HE) staining, and analysis by immunohistochemistry and Western blotting. HE staining showed that the number and percentage of primordial follicles in the rapamycin-treated group were twice the control group (P<0.001). Immunohistochemical analysis showed that mTOR and phosphorylated-p70S6K were extensively expressed in surviving follicles with strong staining observed in the cytoplasm of the oocyte. Western blotting showed decreased expression of phosphorylated mTOR and phosphorylated p70S6K in the rapamycin-treated group, and increased the expression of both SIRT1 and SIRT6 compared to the control group (P<0.05). Taken together, these results suggest that rapamycin may inhibit the transition from primordial to developing follicles and preserve the follicle pool reserve, thus extending the ovarian lifespan of female rats via the modulation of mTOR and sirtuin signalings.

Receptor for advanced glycation end-product (RAGE) gene polymorphism 2245G/A is associated with pro-inflammatory, oxidative-glycation markers and sRAGE in diabetic retinopathy

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Zhi Xiang Ng , Umah Rani Kuppusamy , Tajunisah Iqbal , Kek Heng Chua

Background

Receptor for advanced glycation end-product (RAGE) gene polymorphism 2245G/A is associated with diabetic retinopathy (DR). However, the mechanism on how it affects the disease development is still unclear.

Aim

This study aims to investigate the relationship between 2245G/A RAGE gene polymorphism and selected pro-inflammatory, oxidative-glycation markers in DR patients.

Methods

A total of 371 unrelated type 2 diabetic patients [200 with retinopathy, 171 without retinopathy (DNR)] and 235 healthy subjects were recruited. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism method followed by DNA sequencing. The nuclear and cytosolic extracts from peripheral blood mononuclear cells were used for nuclear factor kappa B (NF-κB) p65 and superoxide dismutase activity measurement respectively. Plasma was used for glutathione peroxidase activity, advanced oxidation protein product (AOPP), monocyte chemoattractant protein (MCP)-1, pentosidine and soluble RAGE (sRAGE) measurements.

Results

DR patients with 2245GA genotype had significantly elevated levels of activated NF-κB p65, plasma MCP-1, AOPP and pentosidine but lower level of sRAGE when compared to DR patients with wild-type 2245GG.

Conclusion

The RAGE gene polymorphism 2245G/A is associated with pro-inflammatory, oxidative-glycation markers and circulating sRAGE in DR patients. Patients with 2245GA RAGE genotype could aggravate DR possibly via NF-κB mediated inflammatory pathway.

Regulation of cellular Cyclin D1 gene by arsenic is mediated through miR-2909

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): M. Sharma , S. Sharma , M. Arora , Deepak Kaul

Arsenic through its ability to regulate genes that link cell cycle control with apoptosis has been widely recognized to play a crucial role in oncogenomics. However, the molecular event by which arsenic affects such genes is far from clear. Here we provide reasonably good evidence to support the view that arsenic exposure to human PBMCs (peripheral blood mononuclear cells) at low concentrations results in the over-expression of miR-2909 within these cells. This over-expressed miR-2909 was found to regulate CCND1 (Cyclin D1) gene expression, within these cells by inducing splice-switching of tumor suppresser CYLD (Cylindromatosis) gene as well as modulation of SP1 (Specificity Protein 1) activity through the repression of KLF4 (Kruppel-like factor4) expression at the translational level. Arsenic dependent regulation of AATF (Apoptosis Antagonizing Transcription factor) and BCL3 (B-cell Lymphoma 3) were also found to be modulated through its capacity to induce miR-2909 expression. Based upon these observations, a novel epigenomic pathway was proposed which may not only be useful in understanding the paradoxical role of arsenic in oncogenomics but also may even be useful in devising various strategies for the treatment/prevention of tumors induced by arsenic.

Ring chromosome 21 presenting with sacrococcygeal teratoma: Prenatal diagnosis, molecular cytogenetic characterization and literature review

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Chih-Ping Chen , Po-Jen Cheng , Shuenn-Dyh Chang , Yi-Xuan Lee , Jin-Chung Shih , Schu-Rern Chern , Peih-Shan Wu , Jun-Wei Su , Yu-Ting Chen , Adam Hwa-Ming Hsieh , Teresa Hsiao-Tien Chen , Li-Feng Chen , Wayseen Wang

We present perinatal findings and molecular cytogenetic characterization of a prenatally detected sacrococcygeal teratoma associated with mosaic r(21). This is the first report of mosaic r(21) presenting with a fetal sacrococcygeal teratoma. We discuss cytogenetic abnormalities associated with fetal sacrococcygeal teratomas.

Screening of high-risk Gaucher disease patients using dried blood spots techniques

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Filippo Vairo , Cristina Netto , Kristiane Michelin Tirelli , Marina Siebert , Maira Burin , Maria Luiza Saraiva-Pereira , Andrea Balreira , Maria Clara Sá Miranda , Zoltan Lukacs , Ida Vanessa D. Schwartz

Single nucleotide polymorphism in CPT1B and CPT2 genes and its association with blood carnitine levels in acute myocardial infarction patients

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Haseeb Ahmad Khan , Abdullah Saleh Alhomida

Ischemic and reperfusion injuries in acute myocardial infarction (AMI) lead to mitochondrial dysfunction in heart cells. Lipid metabolism takes place in mitochondria where carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into matrix to provide substrates for beta-oxidation. We sequenced the coding regions of CPT1B and CPT2 genes to identify the single nucleotide polymorphism (SNP) in 23 AMI patients and 23 normal subjects. We also determined blood carnitine levels in these samples to study the impact of these SNPs on carnitine homeostasis. The sequencing of coding regions revealed 4 novel variants in CPT1B gene (G320D, S427C, E531K, and A627E) and 2 variants in CPT2 gene (V368I and M647V). There were significant increases in total carnitine (54.18±3.11 versus 21.49±1.03μmol/l) and free carnitine (37.78±1.87 versus 10.06±0.80μmol/l) levels in AMI patients as compared to normal subjects. CPT1B heterozygous variants of G320D and S427C among control subjects showed significantly higher levels of total and free carnitine in the blood. The homozygous genotype (AA) of CPT2 variant V368I had significantly less blood carnitine in AMI patients. Serum troponin T was significantly less in GG genotype of CPT1B variant S427C whereas the genotype AA of CPT2 variant V368I showed significantly higher serum troponin T levels. Further studies on large number of patients are necessary to confirm the role of CPT1B and CPT2 polymorphism in AMI.

Specific expression pattern of a novel Otx2 splicing variant during neural differentiation

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 July 2013
Source:Gene, Volume 523, Issue 1

Author(s): Zhongliang Liu , Liankai Chi , Yujiang Fang , Ling Liu , Xiaoqing Zhang

We cloned a new splicing variant of Otx2 gene, Otx2c. Otx2c lacks entire exon 4, most of the region encoding the homeodomain. More importantly, Otx2c harbors an early premature stop codon and bioinformatics analysis prefers it to be a non-protein coding RNA. In addition, this splicing variant is not simply a noise during mRNA processing, since it is mainly expressed in undifferentiated human embryonic stem cells but gradually decreased during differentiation. Therefore, we report here that a single pre-mRNA can generate both coding and non-coding RNAs through alternative splicing and this splicing activity is tightly regulated in different cell contexts.

Three novel antimicrobial peptides from the skin of Rana shuchinae

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Jing Pei , Gang Zhao , Benzhong Wang , Hanjin Wang

Intensive studies have demonstrated that there are many antimicrobial peptides in amphibian skins. Three novel antimicrobial peptides were identified from the skin of the frog, Rana shuchinae. They are named shuchins 3–5. Their sequences were determined as KAYSMPRCKGGFRAVMCWL-NH2, KAYSTPRCKGLFRALMCWL-NH2, and KAYSMPRCKYLFRAVLCWL-NH2 by Edman degradation and mass spectrometry analysis, respectively. They are composed of 19 amino acids (aa) with unique sequences. BLAST search indicated that they showed no similarity to any known peptides or proteins. They are a novel family of antimicrobial peptide. These peptides showed antimicrobial activities against all of tested microorganisms including Gram-positive bacteria, Gram-negative bacteria and fungi. The cDNAs encoding precursors of these peptides were cloned from the skin cDNA library of R. shuchinae. The precursors are composed of 64 amino acid residues including predicted signal peptides, acidic spacer peptides, and mature antimicrobial peptides. The current work identified a novel antimicrobial peptide family.

Unusual features in organisation of capsular polysaccharide-related genes of C. jejuni strain X

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): A.V. Karlyshev , M.A. Quail , J. Parkhill , B.W. Wren

PCR probing of the genome of Campylobacter jejuni strain X using conserved capsular polysaccharide (CPS)-related genes allowed elucidation of a complete sequence of the respective gene cluster (cps). This is the largest known Campylobacter cps cluster (38kb excluding flanking kps regions), which includes a number of genes not detected in other Campylobacter strains. Sequence analysis suggests genetic rearrangements both within and outside the cps gene cluster, a mechanism which may be responsible for mosaic organisation of sugar transferase-related genes leading to structural variability of the capsular polysaccharide (CPS).

Update meta-analysis on MMP-7 −181A>G polymorphism and cancer risk: Evidence from 25 studies

Wed, 15 May 2013 22:14:00 GMT

Publication date: 1 June 2013
Source:Gene, Volume 521, Issue 2

Author(s): Xueling Yang , Ya Liu , Yufeng Yang , Bo Li

Background

The matrix metalloproteinase (MMP) can degrade various components of the extracellular matrix and its functional genetic polymorphism may be associated with cancer development. The common MMP-7 (−181A>G) genetic polymorphism has been reported to be functional and may contribute to genetic susceptibility to cancers. However, the association between MMP-7 (−181A>G) and cancer risk remains inconclusive.

Methods

To better understand the role of MMP-7 (−181A>G) polymorphism in global cancer, we conducted this comprehensive meta-analysis encompassing 6392 cases and 7665 controls.

Results

Overall, the MMP-7 (−181A>G) polymorphism was associated with higher cancer risk. In the stratified analyses, significant associations were found between the MMP-7 (−181A>G) polymorphism and gastric cancer, ESCC and gynecologic cancer. We also observed that the GG genotype might modulate colorectal cancer risk comparing with the AA genotype (OR=1.31[1.02–1.69]). Moreover, a significantly increased cancer risk was found among Asian populations. When stratified by study design, significantly elevated susceptibility to cancer was found among population-based studies.

Conclusions

These findings suggested that the MMP-7 (−181A>G) genetic polymorphism may contribute to the susceptibility of cancers, especially among Asian population.

Using OPLS-DA to find new hypotheses in vast amounts of gene expression data — Studying the progression of cardiac hypertrophy in the heart of aorta ligated rat

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Nina Gennebäck , Linus Malm , Urban Hellman , Anders Waldenström , Stellan Mörner

One of the great problems facing science today lies in data mining of the vast amount of data. In this study we explore a new way of using orthogonal partial least squares-discrimination analysis (OPLS-DA) to analyze multidimensional data. Myocardial tissues from aorta ligated and control rats (sacrificed at the acute, the adaptive and the stable phases of hypertrophy) were analyzed with whole genome microarray and OPLS-DA. Five functional gene transcript groups were found to show interesting clusters associated with the aorta ligated or the control animals. Clustering of “ECM and adhesion molecules” confirmed previous results found with traditional statistics. The clustering of “Fatty acid metabolism”, “Glucose metabolism”, “Mitochondria” and “Atherosclerosis” which are new results is hard to interpret, thereby being possible subject to new hypothesis formation. We propose that OPLS-DA is very useful in finding new results not found with traditional statistics, thereby presenting an easy way of creating new hypotheses.

Widespread, abundant, and diverse TE-associated siRNAs in developing wheat grain

Wed, 15 May 2013 22:14:00 GMT

Publication date: 10 June 2013
Source:Gene, Volume 522, Issue 1

Author(s): Fenglong Sun , Weiwei Guo , Jinkun Du , Zhongfu Ni , Qixin Sun , Yingyin Yao

Small RNAs related to RNA interference are key molecules in many developmental processes, in which they can both regulate developmental gene expression and maintain the integrity of the genome and epigenome. In plants, short interfering RNAs (siRNAs) of 24nt in length are an abundant type of small RNA associated with transposable elements (TEs), other repetitive sequences, and viral defense. One means by which TE-associated siRNAs affect genome integrity is by altering chromatin structure through a process called RNA-directed DNA methylation (RdDM). In this paper, we describe a comparative survey of siRNAs from wheat seedling leaves, seedling roots, young spikelets, and grains at 8 and 15days after pollination (DAP). We find that the general patterns of siRNA distributions are similar across different TEs and within TEs of the same family regardless of tissue, but the relative abundance of 24-nt siRNAs is highest in developing grains. We also find that TEs that are transcriptionally active in endosperm are associated with the highest siRNA abundance not only in grains, but also in other tissues as well. These results suggest that RdDM is an important feature of developing wheat grain and are consistent with the hypothesis that TE expression in endosperm results in increased TE siRNAs, and that RdDM is a conserved feature of plant seed development.

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