Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations

Abstract

In the present study, genotype-phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation.

FIG. 1

Pedigrees of the Dutch families with autosomal recessive hearing impairment and segregation of the TMPRSS3 mutations. Family E is previously described by Cremers et al. (1987). All unaffected sibs were either carrier of one mutant allele or of two wild-type alleles. Square, male; circle, female; open symbol, clinically unaffected; solid symbol, clinically affected; slash, deceased individuals. NT not tested.

FIG. 2

Selection of binaural mean air conduction threshold values of clinically affected family members at different ages, ordered by age (from top left to bottom right) at last visit (Cremers et al. 1987). Family number and sequence number are above each audiogram. Gray background, relatively poorer thresholds.

FIG. 3

a Longitudinal individual measurements of individuals A5, D4, D6, D7, E8, E9, E10, E13, F3, G3, H3, and H5 for each frequency separately (different symbols for each individual; Cremers et al. 1987). A dose–response curve with a variable slope could be obtained for the longitudinal data of individual E10 for each frequency (bold line). b ARTA derived from a longitudinal regression analysis of mean AC threshold levels of individual E10. Italics indicate age in years.

FIG. 4

Single-snapshot measurements of the affected family members of binaural mean phoneme recognition scores against age (left) and against binaural mean pure tone average at 1, 2, and 4 kHz (right; Cremers et al. 1987). The solid regression line covers the cross-sectional analysis. The dotted curve represents presbyacusis and was previously established for patients with presbyacusis. See text for the meaning of the figures and the straight horizontal and vertical lines.

FIG. 5

Molecular modeling for TMPRSS3 missense mutations. Graphic representation of the effect of the p.Ala306Thr and p.Ala426Thr mutations in the serine protease domain (A) and of the p.Ala138Glu and p.Val199Met in the SRCR domain (B). The wild-type residues are depicted in green, while the mutant residues are shown in red. The yellow structure represents a substrate for the serine protease domain (figure made using the model for TMPRSS and YASARA).