title: Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness.
abstract: Approximately 50% of childhood deafness is caused by mutations in specific genes. Autosomal recessive loci account for approximately 80% of nonsyndromic genetic deafness. Here we report the identification of a new transmembrane serine protease (TMPRSS3; also known as ECHOS1) expressed in many tissues, including fetal cochlea, which is mutated in the families used to describe both the DFNB10 and DFNB8 loci. An 8-bp deletion and insertion of 18 monomeric (approximately 68-bp) beta-satellite repeat units, normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes, causes congenital deafness (DFNB10). A mutation in a splice-acceptor site, resulting in a 4-bp insertion in the mRNA and a frameshift, was detected in childhood onset deafness (DFNB8). This is the first description of beta-satellite insertion into an active gene resulting in a pathogenic state, and the first description of a protease involved in hearing loss.
authors.affiliation: Division of Medical Genetics, University of Geneva Medical School, Genève, Switzerland.
authors.forename: H S
authors.initials: HS
authors.lastname: Scott
authors.forename: J
authors.initials: J
authors.lastname: Kudoh
authors.forename: M
authors.initials: M
authors.lastname: Wattenhofer
authors.forename: K
authors.initials: K
authors.lastname: Shibuya
authors.forename: A
authors.initials: A
authors.lastname: Berry
authors.forename: R
authors.initials: R
authors.lastname: Chrast
authors.forename: M
authors.initials: M
authors.lastname: Guipponi
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: S
authors.initials: S
authors.lastname: Asakawa
authors.forename: S
authors.initials: S
authors.lastname: Minoshima
authors.forename: F
authors.initials: F
authors.lastname: Younus
authors.forename: S Q
authors.initials: SQ
authors.lastname: Mehdi
authors.forename: U
authors.initials: U
authors.lastname: Radhakrishna
authors.forename: M P
authors.initials: MP
authors.lastname: Papasavvas
authors.forename: C
authors.initials: C
authors.lastname: Gehrig
authors.forename: C
authors.initials: C
authors.lastname: Rossier
authors.forename: M
authors.initials: M
authors.lastname: Korostishevsky
authors.forename: A
authors.initials: A
authors.lastname: Gal
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
authors.forename: B
authors.initials: B
authors.lastname: Bonne-Tamir
authors.forename: S E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D020451:Contig Mapping; D004252:DNA Mutational Analysis; D004276:DNA, Satellite / Q000235:genetics*; D003638:Deafness / Q000151:congenital* / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007557:Israel; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009363:Neoplasm Proteins; D010154:Pakistan; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D004276:DNA, Satellite; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human