Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness.
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.
Scott
H S
HS
Division of Medical Genetics, University of Geneva Medical School, Genève, Switzerland.
Kudoh
J
J
Wattenhofer
M
M
Shibuya
K
K
Berry
A
A
Chrast
R
R
Guipponi
M
M
Wang
J
J
Kawasaki
K
K
Asakawa
S
S
Minoshima
S
S
Younus
F
F
Mehdi
S Q
SQ
Radhakrishna
U
U
Papasavvas
M P
MP
Gehrig
C
C
Rossier
C
C
Korostishevsky
M
M
Gal
A
A
Shimizu
N
N
Bonne-Tamir
B
B
Antonarakis
S E
SE
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
D004276:DNA, Satellite; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human