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Figure 1 | Human Genomics

Figure 1

From: Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population

Figure 1

Novel mutations responsible for inherited deafness in four kindreds. In each pedigree, filled symbols represent individuals with severe, bilateral, prelingual hearing loss. The mutation found in each family is illustrated by a sequence below the appropriate pedigree, with mutations indicated on the sequences by red arrows. (a) In Family W, hearing loss is linked to markers flanking the serine protease TMPRSS3 on chromosome 21q22.3. Sequence of TMPRSS3 in affected members of the family revealed frameshift 988ΔA (357stop), which abrogates serine protease activity. As predicted by linkage data, all affected relatives in Family W are homozygous for TMPRSS3.988ΔA and all unaffected relatives are heterozygous or wild-type. (b) In Family BR, hearing loss is linked to markers flanking otoancorin on chromosome 16p12.2. The sequence of otoancorin in affected members of the family revealed missense mutation 1067A > T (D356V), a highly non-conservative change that is likely to disrupt the otoancorin transmembrane structure. All affected relatives in Family BR are homozygous for otoancorin 1067A > T (D356V) and all unaffected relatives are heterozygous or wild-type. D356V is the first deafness-associated missense mutation reported in otoancorin. (c) In Family Y, hearing loss is linked to markers flanking pendrin on chromosome 7q31.1. The sequence of pendrin in affected members of the family revealed missense mutation 716T > A (V239D), which leads to cellular mislocalisation of pendrin protein (see Figure 2). All affected relatives in Family Y are homozygous for pendrin 716T > A (V239D) and all unaffected relatives are heterozygous or wild-type. (d) In Family BF, hearing loss is also linked to markers flanking pendrin, but to different alleles than were linked to the phenotype in Family Y. The sequence of pendrin in affected members of Family BF revealed 1001G > T. RT-PCR of pendrin from lymphoblasts of affected relatives of Family BF indicates that 1001G > T alters splicing, leading to insertion of 41 intronic base pairs into the pendrin message and a premature stop at codon 346 (red box). By homology with other sulphate transporters, truncation at this site would abrogate sulphate transporter activity of the protein. All affected relatives in Family BF are homozygous for pendrin 1001G > T and all unaffected relatives are heterozygous or wild-type.

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