Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness

Nat Genet. 2001 Jan;27(1):59-63. doi: 10.1038/83768.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Base Sequence
  • Child
  • Consanguinity
  • Contig Mapping
  • DNA Mutational Analysis
  • DNA, Satellite / genetics*
  • Deafness / congenital*
  • Deafness / enzymology*
  • Deafness / epidemiology
  • Deafness / genetics
  • Exons / genetics
  • Female
  • Frameshift Mutation / genetics
  • Genes, Recessive / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Israel
  • Male
  • Membrane Proteins*
  • Molecular Sequence Data
  • Mutagenesis, Insertional / genetics*
  • Neoplasm Proteins*
  • Pakistan
  • Pedigree
  • RNA Splice Sites / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Sequence Alignment
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism

Substances

  • DNA, Satellite
  • Membrane Proteins
  • Neoplasm Proteins
  • RNA Splice Sites
  • RNA, Messenger
  • Serine Endopeptidases
  • TMPRSS3 protein, human

Associated data

  • GENBANK/AB038157
  • GENBANK/AB038158
  • GENBANK/AB038159
  • GENBANK/AB038160
  • GENBANK/AP001623