The goal of the Laboratory of Molecular Genetics, Section on Human Genetics is to identify and study the function of mutated genes for human hereditary syndromic and nonsyndromic deafness. A new study begins with the ascertainment of large families in which deafness appears to be inherited either as a monogenic dominant or as monogenic recessive trait. We then search for linkage of the deafness to 950,000 SNP markers across the human genome. During the past year we ascertained several large families segregating deafness, mapped novel deafness loci, one of which is S1PR2, for nonsyndromic deafness DFNB68, a collaboration with Dr. Leal at Baylor College of Medicine. Staff in the LMG have been working on the following projects, some of which were completed in the past year and have been published, are in press or are likely to be published in the near future. 1. Eleven years ago, DFNB32 was mapped to chromosome 1 by another research group, but the underlying gene was never reported. In five of our consanguineous families segregating recessively inherited nonsyndromic deafness linked to markers for the DFNB32 locus, we have identified three truncating mutations, a splice site mutation and a missense mutation in a gene in our refined DFNB32 interval. Ayesha Imtiaz, PhD, a fellow in the LMG, is exploring the function of the DFNB32 gene in the auditory system. Drs. Imtiaz and Belyantseva are using a conditional ko mouse of this gene that we have engineered to explore its function in the auditory system. As a collaboration with Dr. Katie Kindt, we have constructed zebrafish models of the DFNB32 gene to probe its function. 2. 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. Using next-generation sequencing technology Atteeq rehman, PhD, a fellow in the LMG, identified mutations in CLPP encoding a mitochondrial chambered proteas. 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. This paper was published earlier in 2013 (Jenkinson, Rehman and Walsh et al., AJHG 2013). Atteeq is the co-first author and Friedman is the co-communicating author with William Newman, MD, PhD. We are continuing to work on the functions of CLPP in the auditory system and have engineered TALEN-edited missions mutations in the mouse Clpp gene that recapitulate two of the missions mutations associated with Perrault syndrome. We also have a Clpp knockout mouse obtained as a collaboration with Dr. Suzana Gispert. Using these three animal models, the goal is to understand the essential function of CLPP in the inner ear. The mouse CLPP project is a collaboration with Dr. Lisa Cunningham. 3. Large families segregating nonsyndromic deafness and deafness associated with other clinical features (syndrome) are being ascertained in Pakistan. In the LMG staff are identifying the genetic causes of the deafness and are uncovering novel mutated genes associated with deafness. The wild type function of these genes in the auditory system is a specific aim of this sub-project. 4. The gene responsible for human deafness DFNB28 human deafness was identified as TRIOBP (Kitajiri et al., Cell, 2010). TRIOBP encodes three distinct proteins that arise from alternative splicing of TRIOBP transcripts. TRIOBP isoforms are referred to as TRIOBP-1, TRIOBP-4 and TRIOBP-5. Loss of TRIOBP-1 causes embryonic lethality in mouse. Simultaneous loss of TRIOBP4 and TRIOBP-5 causes deafness as a result of the inability of hair cells to develop stereocilia rootlets. Purified TRIOBP-4 tightly bundles F-actin typical of stereocilia rootlets. The individual function of TRIOBP-5 is not known. We have engineered mice that do not express function TRIOBP-5 and they are deaf but develop rootlets. The cause of deafness due to the loss of TRIBP-5 is being explored by Dr. Belyantseva in collaboration with Shin-ichiro Kitajiri, MD, PhD who is a PI of a laboratory in Japan.
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