Genetics of Hearing Loss in Middle Eastern Families

中东家庭听力损失的遗传学

• 批准号: 7627319
• 负责人: MARY-CLAIRE KING
• 金额: $ 50.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-07 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627319
• 关键词: Address; Alleles; Amino Acid Sequence; Biology; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Cochlea; Collaborations; Development; ES Cell Line; Ear; Enrollment; Family; Frequencies; Genes; Genetic; Genome Scan; Genotype; Goals; Hearing; Hearing Impaired Persons; Human; Individual; Inherited; Knock-in Mouse; Labyrinth; Link; Maps; Middle East; Molecular Profiling; Morphology; Mus; Mutant Strains Mice; Mutation; Names; Nonsense Mutation; Penetrance; Peptide Sequence Determination; Phenotype; Population; Potassium Channel; Protein Isoforms; Proteins; Recessive Genes; Series; Testing; Transcript; Transforming Protein ERG; deafness; hearing impairment; human GJB2 protein; kindred; mouse development; mouse model; mutant; novel; positional cloning; success

DESCRIPTION (provided by applicant): The goal of this project is to find and characterize genes responsible for hereditary hearing impairment (HHI) in highly informative Middle Eastern kindreds. Genes identified in these consanguineous families are important to the non-consanguineous U.S. deaf population because all genes for HHI illuminate universal features of hearing biology and because such genes often harbor other mutations leading to recessive or dominant HHI in populations worldwide. We have thus far identified DFNA15 as POU4F3, DFNB30 as MYO3A, and now DFNB28 as a novel isoform of TARA, which we name OTOTARA. We are developing a mouse model of the MYO3A/DFNB30 nonsense mutation. In two other kindreds, we mapped genes for hearing loss to small intervals on chromosomes 2q31 and 11q14.3-q21. These regions do not harbor known deafness genes, so these kindreds will reveal two more novel genes for HHI. In four other families, we identified new alleles of known deafness genes, suggesting that genetic hearing loss in this population is similar to that elsewhere. In the 156 families with HHI enrolled in our project, GJB2 (connexin 26) is responsible for HHI in only 17 (11%) of families, reflecting the high frequency of HHI due to other genes. In the next cycle of this project, our collaboration proposes: (1) to further characterize wildtype and mutant OTOTARA (2) to identify genes for recessive, nonsyndromic HHI on chromosomes 2q31 and 11q14.3-q21 (3) to undertake positional identification of genes for HHI in four additional kindreds (4) to complete the MYO3A/DFNB30 knock-in mouse and characterize its phenotype The strengths of this collaboration are the enthusiastic participation in the project of extended informative kindreds with HHI, the large number of these kindreds likely to carry mutations in heretofore unknown hearing-related genes, and our demonstrated success in mapping, identifying, and characterizing genes for HHI in these families.

描述（由申请人提供）：该项目的目标是在信息丰富的中东人种中发现和表征与遗传性听力障碍（HHI）有关的基因。在这些近亲家庭中发现的基因对非近亲美国聋人群体很重要，因为所有的HHI基因都阐明了听力生物学的普遍特征，因为这些基因通常包含其他突变，导致世界范围内人群的隐性或显性HHI。到目前为止，我们已经确定DFNA15为POU4F3， DFNB30为MYO3A，现在DFNB28是TARA的一种新的异构体，我们将其命名为OTOTARA。我们正在开发MYO3A/DFNB30无义突变的小鼠模型。在另外两种类型中，我们将听力损失的基因定位到染色体2q31和11q14.3-q21上的小间隔。这些区域没有已知的耳聋基因，因此这些类型将揭示两个新的HHI基因。在另外四个家庭中，我们发现了已知耳聋基因的新等位基因，这表明该人群的遗传性听力损失与其他地方相似。在我们项目纳入的156个HHI家族中，GJB2 （connexin 26）仅在17个（11%）家族中负责HHI，反映了其他基因导致HHI的高频率。在这个项目的下一个周期中，我们的合作提议：