The goal of the Section on Human Genetics is to identify and study the function of mutated genes for human hereditary deafness. This work begins with the ascertainment of large families in which deafness appears to be inherited either as a dominant or a recessive trait. We then search for linkage of the deafness to genetic markers for the known (already reported) syndromic, DFNA (dominant) and DFNB (recessive) loci. If linkage to the known deafness loci can be excluded, we initiate a genome-wide screen to search for novel deafness loci followed by work to identify the causative gene. During the past year we ascertained several large families segregating deafness, mapped a novel deafness locus, and identified a novel gene for nonsyndromic deafness. Sections of the following projects were completed in the past year and have been published or are in press and likely to be published in 2012. 1. We recently mapped a novel nonsyndromic deafness locus (DFNB81) to chromosome 19p, which is distinct from the closely linked DFNB72 locus (Rehman et al., 2011 EJHG). Mutations of GIPC3 are responsible for DFNB72 deafness. In collaboration with Drs. Suzanne Leal and William Newman, we are working to identify the mutated gene underlying DFNB81 deafness using next-generation sequencing technology. DFNB81 deafness was initially presumed to be nonsyndromic. However, further clinical chactareization of the affected subjects indicates Perrault syndrome characterized by hearing loss and female gonadal dysgenesis. 2. We mapped a novel locus for nonsyndromic deafness to chromosome 16p. The locus is designated DFNB86 (Ali et al., 2011). We are working to identify the mutated gene underlying DFNB86 deafness gene using advanced sequencing methodologies. 3. Grhl2-TMinsC/+ is a mouse model of DFNA28 human progressive hearing loss, which we reported ten years ago (Peters et al., 2002). A goal of our present study is to understand the function of the GRHL2 transcription factor in the auditory system. To that end, we have performed ChIP-Seq experiments using our own and commercially available antibodies to GRHL2, in a variety of tissues and cell types. In collaboration with Drs. Maria Ramirez and Saaket Varma at Boston University Medical School, and as a way to validate this technology in our laboratory, we extended our ChIP and expression analyses to include developing lung buds and the MLE15 cell line derived from adult mouse lung. GRHL2 is required for normal lung development. Varma et al. 2012, (Morell and Friedman are co-authors) showed that GRHL2 and NKX2-1 transactive each other and form a regulatory loop defining the critical transition from a type II cell type (cuboidal) to type I (squamous) in the lung alveolus. We are making a more comphrehensive survey of GRHL2 regulatory targets in the lung as compared to the auditory system using ChIP-Seq and our AB5500 sequencer. 5. Nonsyndromic deafness DFNB48 and a novel type 1 Usher syndrome were previously genetically mapped by us to an overlapping interval on chromosome 15q21-q23 (Ahmed et al., 2009). We recently demonstrated that mutations associated with DFNB48 and USH1J are allelic and that the causative gene encodes a calcium binding protein (Riazuddin et al., 2012, Nature Genetics, in press).

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National Institute on Deafness and Other Communication Disorders
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Imtiaz, Ayesha; Belyantseva, Inna A; Beirl, Alisha J et al. (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27:780-798
Yousaf, Rizwan; Ahmed, Zubair M; Giese, Arnaud Pj et al. (2018) Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. J Clin Invest 128:1509-1522
Ahmed, Zubair M; Jaworek, Thomas J; Sarangdhar, Gowri N et al. (2018) Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment. J Med Genet 55:479-488
Nakano, Yoko; Kelly, Michael C; Rehman, Atteeq U et al. (2018) Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness. Cell 174:536-548.e21
Yousaf, Rizwan; Gu, Chunfang; Ahmed, Zubair M et al. (2018) Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet 14:e1007297
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Chattaraj, Parna; Munjal, Tina; Honda, Keiji et al. (2017) A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct. J Med Genet 54:665-673
Mauriac, Stephanie A; Hien, Yeri E; Bird, Jonathan E et al. (2017) Defective Gpsm2/G?i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome. Nat Commun 8:14907
Naz, Sadaf; Imtiaz, Ayesha; Mujtaba, Ghulam et al. (2017) Genetic causes of moderate to severe hearing loss point to modifiers. Clin Genet 91:589-598

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