The heritable trait of nonsyndromic deafness follows simple Mendelian laws of inheritance with extreme heterogeneity; many different genes, when mutated, can alter one's ability to hear. There are now 33 recessive loci published on the Hereditary Hearing Loss Homepage (http://dnalab-www.uia.ac.be/dnalab/hhh/) and we are aware of 4 additional loci not yet published. We take the numbers of families that do not link to these known loci as an indication that there are still many additional unknown loci responsible for nonsyndromic deafness. Under the current protocol, deafness loci segregating among consanguineous families from Pakistan, India and Iran were ascertained. Most families consist of at least three deaf siblings or 2 deaf first cousins (simulated LOD scores with FastSLINK are greater than or equall to 2). In a typical family, the parents are either first cousins or an uncle married to his niece. Some of these families segregate loci in which an actual gene has been identified such as DFNB1, DFNB2, DFNB3, DFNB4, DFNB6, DFNB7/DFNB11, DFNB8/DFNB10, DFNB9, DFNB12, DFNB16, DFNB18, DFNB21, DFNB22, and DFNB29. Other families help refine the linkage localization of a known locus, and yet others are unlinked and will allow for the localization of new loci. This year we have mapped several new loci and identified several additional genes contributing to nonsyndromic hereditary deafness. DFNB6 is caused by mutations in the novel gene, TMIE, (located at chromosome 3p21) which co-segregates with deafness in at least five different consanguineous families from India and Pakistan. The refined linkage region includes the gene coding for TMIE, which was found mutated in all five families. These mutations were not found among several hundred ethnically matched control samples. This discovery was possible with the help of Dr. David Kohrman, who found that Spinner mice have mutations in Tmie. On the basis of conserved synteny between distal mouse chromosome 9 and human chromosome 3p Tmie was proposed as the cause of DFNB6 deafness in humans. The data now confirms that TMIE is mutated in families segregating hereditary deafness. Deafness was the sole clinical feature in common among those with mutations in this gene, though one family also presented with a delay of independent ambulation and may reflect an underlying vestibular defect. Additional mutations were found in the USH1C gene, causing either USH1C or DFNB18. The first demonstration that DFNB18 and USH1C are allelic. Progress is being made in identifying additional exons of PCDH15 and towards the identification of DFNB26 and DFNM1. Collaborations have continued with other NIH intramural investigators to find families from Pakistan with inherited traits of interest, such as stuttering, and retinitis pigmentosa.
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