Genetic Mapping Refines DFNB3 to 17p11.2, Suggests Multiple Alleles of DFNB3, and Supports Homology to the Mouse Model shaker-2

Abstract

The nonsyndromic congenital recessive deafness gene, DFNB3, first identified in Bengkala, Bali, was mapped to a approximately 12-cM interval on chromosome 17. New short tandem repeats (STRs) and additional DNA samples were used to identify recombinants that constrain the DFNB3 interval to less, similar6 cM on 17p11.2. Affected individuals from Bengkala and affected members of a family with hereditary deafness who were from Bila, a village neighboring Bengkala, were homozygous for the same alleles for six adjacent STRs in the DFNB3 region and were heterozygous for other distal markers, thus limiting DFNB3 to an approximately 3-cM interval. Nonsyndromic deafness segregating in two unrelated consanguineous Indian families, M21 and I-1924, were also linked to the DFNB3 region. Haplotype analysis indicates that the DFNB3 mutations in the three pedigrees most likely arose independently and suggests that DFNB3 makes a significant contribution to hereditary deafness worldwide. On the basis of conserved synteny, mouse deafness mutations shaker-2 (sh2) and sh2J are proposed as models of DFNB3. Genetic mapping has refined sh2 to a 0.6-cM interval of chromosome 11. Three homologous genes map within the sh2 and DFNB3 intervals, suggesting that sh2 is the homologue of DFNB3.

Sign-spatiality in Kata Kolok

“…Therefore, we need to take into account the relative reliability of these sources. In subsequent sections, an attempt will nevertheless be made to estimate the age of Kata Kolok, informed by an evaluation of anthropological evidence (Hinnant 2000;Marsaja 2008:53-60) and genetic research stemming from the early 1990s Morell et al 1995;Winata et al 1995;Liang et al 1998;Friedman et al 2000). I argue that Kata…”

“…The family tree, which was produced after extensive anthropological fieldwork, concludes that this first deaf individual was followed by a generation of no deaf children being born, but with multiple deaf villagers in successive generations, thus sustaining the communicative need for sign language. Figure 2.3 presents the family tree produced by Liang et al (1998). This diagram is still largely accurate, although in recent years individuals 126, 127, and 58 have passed away.…”

“…The genealogical tree created by Liang et al (1998) (Senghas, Kita, & Özyürek 2004). Ultimately, the most appropriate measures to chart a sign language's development would appear to be its time depth in years and the increase of its users across multiple cohorts of signers.…”

Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome

“…Mutations in myosin XVA are responsible for the shaker 2 (sh2) phenotype in mice and nonsyndromic autosomal recessive profound hearing loss DFNB3 in humans (Friedman et al 1995). A genome-wide homozygosity mapping strategy has localized DFNB3 to 17p, which has subsequently been refined to a 3-cM interval within the 17p11.2 Smith-Magenis syndrome interval (SMS, MIM 182290;Friedman et al 1995;Liang et al 1998). Myosin XVA was identified through bacterial artificial chromosome rescue of the shaker 2 deafness phenotype, and its human ortholog was shown to underlie DFNB3 deafness Wang et al 1998).…”

Genomic organisation of the ∼1.5 Mb Smith-Magenis syndrome critical interval: Transcription map, genomic contig, and candidate gene analysis

“…8,16 ± 21 This region of 17p11.2 is very gene-rich. Within the critical deletion region, eleven genes have previously been reported: the human homologue of the Drosophila flightless-I gene (FLII); cytosolic serine hydroxymethyltransferase (SHMT1); 21,23 the human homologue of Drosophila lethal 2 giant larva (LLGL1); 18 topoisomerase IIIa (TOP3A); 19,24,25 elongation factor 1a (EEF1A3); 8 sterol regulatory element binding protein 1 (SREBF1); 8 myosin 15 (MYO15A); 26,27 phosphatidylethanolamine-N-methyltransferase 2 (PEMT2); 8,20 signalosome subunit 3 of the COP9 signalosome (COP53, SGN3); 28,29 developmentally-regulated GTP-binding protein 2 (DRG2); 30 and deoxyribonucleotidase-2 (NT5M, formerly dNT-2). 31 Many of these genes have been wellcharacterised and the effect of hemizygosity of several genes has been assessed in a variety of systems; yet there still remains no single excellent candidate gene for the SMS phenotype.…”