Figure 1.
Filled symbols for males (squares) and females (circles) represent affected individuals, and empty, unaffected ones. An arrow denotes the proband. A symbol with dot indicates the individual younger than the average age of onset, who is mutation carrier but does not present hearing loss (a mutation carrier). Symbols with asterisk are individuals who have had clinical and genetic tests.
Figure 2.
Audiograms of the proband (V:6) and the a five-year-old patient (VI:4).
Symbols “o” and “x” denote air conduction pure-tone thresholds at different frequencies in the right and left ear. dB, decibels; Hz, Hertz. The dashed line represent the audiograms detected in 2005 when the proband (V:6) was 23 years old. Audiological examination with solid line was performed in 2012.
Table 1.
Summary of the clinical data for all individuals with p.M418K in family 1304.
Figure 3.
ABR results performed to the proband (V:6), a five-year-old patient (VI:4), a two-year-old carrier (VI:5) of p.M418K and a five-year-boy (VI:18) with normal hearing and wildtype genotype.
ABR was performed using click stimulus.
Figure 4.
Gene identified in family 1304 with autosomal dominant progressive hearing loss.
A: Schematic physical and genetic maps of DFNA36 locus on the 9q31chromosomal region. The TMC1 gene is indicated. B: Schematic structure of TMC1 gene. TMC1 gene has 24 exons. Mutation of p.M418K and p.G417R locate in exon16, and mutation of p.D572N and p.D572H are in exon19. C: Sequencing chromatograms of TMC1 showing the heterozygous substitution, c.1253A>T in affected individuals (upper panel) compared with that of normal control (lower panel). The mutated nucleotides are marked by triangles. The predicted amino acid changes and surrounding ones are indicated above the sequences. D: Multiple amino acid sequences alignment of TMC1 and its paralog of TMC2 using ClustalW software. The conservation analysis shows that p.M418K(arrow) mutation in TMC1 located in a highly conserved position comparing with the corresponding sequences of human, mouse, rat, macaque, dog, pig, chick, human TMC2 and mouse Tmc2. E: A schematic diagram of TMC1 protein predicted by TMHMM2.0 containing six transmembrane domains, a cytoplasmic N and C termini. All reported DFNA36 mutations or residual are indicated. Mutation of p.M418K found in this study is located in the second extracellular loop between the third and the fourth transmembrane domain.
Table 2.
Filter process for the variants found by whole exome sequencing.