非综合征型遗传性耳聋基因的研究进展及相关网络资源

耳聋是一种最常见的人类感觉系统缺陷,70%的遗传性耳聋属于非综合征型听力缺损。据估计非综合征型遗传性耳聋基因总数在100个以上,迄今已经有大约80个基因座被绘制于人类染色体上,至少23个基因得鉴定。本文系统地介绍了已鉴定的23个非综合征型耳聋基因,并列举了与遗传性耳聋相关的部分网络资源以供参考。 Abstract:Deafness is the most prevalent sensory system impairment of human,and 70% of genetic deafness belongs to nonsyndromic hearing impairment.The total number of genes involved in nonsyndromic hereditary deafness has been estimated to above 100.So far,approximate 80 loci have been mapped to human chromosome,and 23 genes have been identified.In this article,these 23 genes were summarized systematically and some databases about hereditary deafness were provided for reference.     

mtDNA mutation C1494T, haplogroup A, and hearing loss in Chinese

Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To test this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL.     

Genetic risk factors for nonsyndromic cleft lip with or without cleft palate in a Mesoamerican population: Evidence for IRF6 and variants at 8q24 and 10q25

INTRODUCTION: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all birth defects. NSCL/P has a multifactorial etiology that includes both genetic and environmental factors. The IRF6 gene and three further susceptibility loci at 8q24, 10q25, and 17q22, which were identified by a recent genome‐wide association scan (GWAS), are confirmed genetic risk factors for NSCL/P in patients of European descent. METHODS: A case‐control association study was performed to investigate whether these four risk loci contribute to NSCL/P in a Mesoamerican population using four single nucleotide polymorphisms to represent IRF6 and the three novel susceptibility loci. A total of 149 NSCL/P patients and 303 controls of Mayan origin were included. RESULTS: Single marker analysis revealed a significant association between NSCL/P and risk variants in IRF6 and the 8q24 and 10q25 loci. In contrast to previous findings, the association at the 8q24 locus was driven solely by homozygote carriers of the risk allele. This suggests that this locus might act in a recessive manner in the Mayan population. No evidence for association was found at the 17q22 locus. This may have been attributable to the limited power of the sample. CONCLUSION: These results suggest that IRF6 and the 10q25 and 8q24 loci confer a risk for the development of NSCL/P in persons of Mayan origin. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.     

A Novel missense mutation of COL2A1 gene in a large family with stickler syndrome type I

Stickler syndrome type I (STL1, MIM 108300) is characterized by ocular, auditory, skeletal and orofacial manifestations. Nonsyndromic ocular STL1 (MIM 609508) characterized by predominantly ocular features is a subgroup of STL1, and it is inherited in an autosomal dominant manner. In this study, a novel variant c.T100>C (p.Cys34Arg) in COL2A1 related to a large nonsyndromic ocular STL1 family was identified through Exome sequencing (ES). Bioinformatics analysis indicated that the variant site was highly conserved and the pathogenic mechanism of this variant may involve in affected structure of chordin‐like cysteine‐rich (CR) repeats of ColIIA. Minigene assay indicated that this variant did not change alternative splicing of exon2 of COL2A1. Moreover, the nonsyndromic ocular STL1 family with 16 affected members showed phenotype variability and certain male gender trend. None of the family members had hearing loss. Our findings would expand the knowledge of the COL2A1 mutation spectrum, and phenotype variability associated with nonsyndromic ocular STL1. Search for genetic modifiers and related molecular pathways leading to the phenotype variation warrants further studies.     

Functional modulation of AMP-activated protein kinase by cereblon

Mutations in cereblon (CRBN), a substrate binding component of the E3 ubiquitin ligase complex, cause a form of mental retardation in humans. However, the cellular proteins that interact with CRBN remain largely unknown. Here, we report that CRBN directly interacts with the α1 subunit of AMP-activated protein kinase (AMPK α1) and inhibits the activation of AMPK activation. The ectopic expression of CRBN reduces phosphorylation of AMPK α1 and, thus, inhibits the enzyme in a nutrient-independent manner. Moreover, AMPK α1 can be potently activated by suppressing endogenous CRBN using CRBN-specific small hairpin RNAs. Thus, CRBN may act as a negative modulator of the AMPK signaling pathway in vivo.     

OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia

Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotypephenotype associations, the OSBPL2-disrupted Bama miniature(BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer(SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss(HL) with degeneration/apoptosis of cochlea hair cells(HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet(HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss(NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.