Genetics of Hearing Loss in Middle Eastern Families

描述(由申请者提供)：本项目的目标是在信息丰富的中东家庭中寻找和鉴定遗传性听力障碍(HHI)的基因。在这些血缘关系密切的家庭中发现的基因对非血缘关系的美国聋人群体来说很重要，因为所有的HHI基因都揭示了听力生物学的普遍特征，而且这些基因通常含有其他突变，导致世界各地的人群中出现隐性或显性HHI。到目前为止，我们已经确定DFNA15为POU4F3，DFNB30为MYO3A，现在DFNB28为Tara的一个新的异构体，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。在另外两个家族中，我们将听力损失的基因定位在染色体2q31和11q14.3-q21上。这些区域没有已知的耳聋基因，因此这些家族将揭示另外两个新的HHI基因。在其他四个家庭中，我们发现了已知耳聋基因的新等位基因，这表明这个群体的遗传性听力损失与其他地方的类似。在我们研究的156个HHI家系中，GJB2(连接蛋白26)只在17个(11%)家系中负责HHI，这反映了其他基因导致HHI的频率很高。在该项目的下一个周期中，我们的合作提出： (1)进一步鉴定野生型和突变型耳廓 (2)鉴定染色体2q31和11q14.3-q21上的隐性、非综合征HHI基因 (3)对新增的四个家系进行HHI基因的定位鉴定 (4)MYO3A/DFNB30基因敲除小鼠的建立及表型鉴定 这一合作的优势在于积极参与HHI的扩展信息家系项目，这些家系中有大量可能携带迄今未知的听力相关基因突变，以及我们在这些家庭中HHI基因的定位、鉴定和表征方面取得的成功。

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.