Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients

Abstract

Two loci for nonsyndromic recessive deafness located on chromosome 21q22.3 have previously been reported, DFNB8 and DFNB10. Recently a gene which encodes a transmembrane serine protease, TMPRSS3 or ECHOS1, was found to be responsible for both the DFNB8 and DFNB10 phenotypes. To determine the contribution of TMPRSS3 mutations in the general congenital/childhood nonsyndromic deaf population we performed mutation analysis of the TMPRSS3 gene in 448 unrelated deaf patients from Spain, Italy, Greece, and Australia who did not have the common 35delG GJB2 mutation. From the 896 chromosomes studied we identified two novel pathogenic mutations accounting for four mutant alleles and at least 16 nonpathogenic sequence variants. The pathogenic mutations were a 1-bp deletion resulting in a frameshift and an amino acid substitution in the LDLRA domain of TMPRSS3. From this and another study we estimate the frequency of TMPRSS3 mutations in our sample as 0.45%, and approximately 0.38% in the general Caucasian childhood deaf population. However, TMPRSS3 is still an important contributor to genetic deafness in populations with large consanguineous families.

TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss

“…c.207delC variant was so far reported in homozygous state in one Spanish [8], one Dutch [16], 6 Pakistani and 8 Newfoundland patients, each from one family [17]. In compound heterozygous state, the mutation was reported in one Greek [8], one Dutch [16] and 2 Newfoundland patients [17].…”

“…Estimated frequency of TMPRSS3 mutations in general childhood Caucasian deaf population is 0.38 % [8]. c.207delC variant was so far reported in homozygous state in one Spanish [8], one Dutch [16], 6 Pakistani and 8 Newfoundland patients, each from one family [17].…”

“…Mutations in TMPRSS3 gene encoding transmembrane serine protease are associated with two ARNSHL phenotypes, DFNB8 with childhood onset and DFNB10 where hearing loss is congenital and severe [7]. TMPRSS3 mutations are predicted to account for \1 % of ARNSHL in Caucasians [8] but are more frequent among Pakistani (1.8 %) [9], Tunisian (5 %) [10], Korean (5.9 %) [11] and especially Turkish patients (12 %) [12].…”

An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss

“…TMPRSS3, a member of the TMPRSS family, causes nonsyndromic recessive deafness when inactivated by pathogenic mutations [Ben-Yosef et al, 2001;Masmoudi et al, 2001;Scott et al, 2001;Guipponi et al, 2002;Wattenhofer et al, 2002Wattenhofer et al, , 2005Lee et al, 2003;Hutchin et al, 2005]. The involvement of TMPRSS3 in hearing loss suggests the possible implication of other TMPRSS members, as shown for members of the myosin superfamily Weil et al, 1995;Donaudy et al, 2003].…”

“…In addition, these membrane-spanning proteins have cytoplasmic N-terminal domains, suggesting possible functions in intracellular signal transduction [Wu, 2003]. Recently, we and others have shown that mutations in TMPRSS3 were responsible for both familial and sporadic forms of nonsyndromic recessive deafness [Ben-Yosef et al, 2001;Masmoudi et al, 2001;Scott et al, 2001;Wattenhofer et al, 2002Wattenhofer et al, , 2005Ahmed et al, 2004;Hutchin et al, 2005]. Genes involved in deafness can be grouped into functional categories (ion channels, transcription factors, motor molecules, extracellular matrix components, and cytoskeletal components).…”