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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Faridi, Rabia; Rehman, Atteeq U; Morell, Robert J et al. (2016) Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome. Clin Genet :
Rehman, Atteeq U; Bird, Jonathan E; Faridi, Rabia et al. (2016) Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness. Hum Mutat 37:991-1003
Santos-Cortez, Regie Lyn P; Faridi, Rabia; Rehman, Atteeq U et al. (2016) Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2. Am J Hum Genet 98:331-8
Imtiaz, Ayesha; Maqsood, Azra; Rehman, Atteeq U et al. (2016) Recessive mutations of TMC1 associated with moderate to severe hearing loss. Neurogenetics 17:115-23
Brewer, Carmen C; Zalewski, Christopher K; King, Kelly A et al. (2016) Heritability of non-speech auditory processing skills. Eur J Hum Genet 24:1137-44
Rehman, A U; Friedman, T B; Griffith, A J (2016) Unresolved questions regarding human hereditary deafness. Oral Dis :
Naz, S; Imtiaz, A; Mujtaba, G et al. (2016) Genetic causes of moderate to severe hearing loss point to modifiers. Clin Genet :
Simon, Mariella; Richard, Elodie M; Wang, Xinjian et al. (2015) Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLoS Genet 11:e1005097
Mujtaba, Ghulam; Schultz, Julie M; Imtiaz, Ayesha et al. (2015) A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss. J Med Genet 52:548-52
Chien, Wade W; Isgrig, Kevin; Roy, Soumen et al. (2015) Gene therapy restores hair cell stereocilia morphology in inner ears of deaf whirler mice. Mol Ther :

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