Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3.
Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterized by progressive hearing loss, severe retinal degeneration, and variably present vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibrium analyses in Finnish carriers of a putative founder mutation, the critical region was narrowed to 250 kb, of which we sequenced, assembled, and annotated 207 kb. Two novel genes-NOPAR and UCRP-and one previously identified gene-H963-were excluded as USH3, on the basis of mutational analysis. USH3, the candidate gene that we identified, encodes a 120-amino-acid protein. Fifty-two Finnish patients were homozygous for a termination mutation, Y100X; patients in two Finnish families were compound heterozygous for Y100X and for a missense mutation, M44K, whereas patients in an Italian family were homozygous for a 3-bp deletion leading to an amino acid deletion and substitution. USH3 has two predicted transmembrane domains, and it shows no homology to known genes. As revealed by northern blotting and reverse-transcriptase PCR, it is expressed in many tissues, including the retina.
Joensuu
T
T
The Folkhälsan Institute of Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Hämäläinen
R
R
Yuan
B
B
Johnson
C
C
Tegelberg
S
S
Gasparini
P
P
Zelante
L
L
Pirvola
U
U
Pakarinen
L
L
Lehesjoki
A E
AE
de la Chapelle
A
A
Sankila
E M
EM
D000015:Abnormalities, Multiple / Q000235:genetics*; D001483:Base Sequence; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003001:Cloning, Molecular; D020451:Contig Mapping; D003638:Deafness / Q000235:genetics*; D020224:Expressed Sequence Tags; D005260:Female; D005387:Finland; D018703:Founder Effect; D020869:Gene Expression Profiling; D008040:Genetic Linkage / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics*; D013577:Syndrome
C437067:CLRN1 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger