title: 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.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands. N.Weegerink@kno.umcn.nl
authors.forename: Nicole J D
authors.initials: NJ
authors.lastname: Weegerink
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Susanne
authors.initials: S
authors.lastname: Granneman
authors.forename: Ronald J E
authors.initials: RJ
authors.lastname: Pennings
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Mariet
authors.initials: M
authors.lastname: Elting
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Ronald J C
authors.initials: RJ
authors.lastname: Admiraal
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Henricus P M
authors.initials: HP
authors.lastname: Kunst
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001301:Audiometry, Pure-Tone; D001302:Audiometry, Speech; D002648:Child; D002675:Child, Preschool; D019929:Cochlear Implantation; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006312:Hearing Loss, Bilateral / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics*; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human