TY - JOUR
T1 - A novel gene for Usher syndrome type 2
T2 - Mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss
AU - Ebermann, Inga
AU - Scholl, Hendrik P.N.
AU - Charbel Issa, Peter
AU - Becirovic, Elvir
AU - Lamprecht, Jürgen
AU - Jurklies, Bernhard
AU - Millán, José M.
AU - Aller, Elena
AU - Mitter, Diana
AU - Bolz, Hanno
N1 - Funding Information:
Acknowledgments Supported by grants BO 2954/1-1 (Deutsche Forschungsgemeinschaft) and Koeln Fortune Program, grant 113/2004 (Faculty of Medicine, University of Cologne), to H.B., and by Heisenberg fellowship SCHO 734/2-1 (Deutsche Forschungsgemeinschaft) and EU FP6, Integrated Project “EVI-GENORET” (LSHG-CT-2005-512036), to H.P.N.S. We are indebted to the family who has participated in this study.
PY - 2007/4
Y1 - 2007/4
N2 - Usher syndrome is an autosomal recessive condition characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP). The seven proteins that have been identified for Usher syndrome type 1 (USH1) and type 2 (USH2) may interact in a large protein complex. In order to identify novel USH genes, we followed a candidate strategy, assuming that mutations in proteins interacting with this "USH network" may cause Usher syndrome as well. The DFNB31 gene encodes whirlin, a PDZ scaffold protein with expression in both hair cell stereocilia and retinal photoreceptor cells. Whirlin represents an excellent candidate for USH2 because it binds to Usherin (USH2A) and VLGR1b (USH2C). Genotyping of microsatellite markers specific for the DFNB31 gene locus on chromosome 9q32 was performed in a German USH2 family that had been excluded for all known USH loci. Patients showed common haplotypes. Sequence analysis of DFNB31 revealed compound heterozygosity for a nonsense mutation, p.Q103X, in exon 1, and a mutation in the splice donor site of exon 2, c.837+1G>A. DFNB31 mutations appear to be a rare cause of Usher syndrome, since no mutations were identified in an additional 96 USH2 patients. While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function. We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. Moreover, this is the first case of USH2 that is allelic to non-syndromic deafness.
AB - Usher syndrome is an autosomal recessive condition characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP). The seven proteins that have been identified for Usher syndrome type 1 (USH1) and type 2 (USH2) may interact in a large protein complex. In order to identify novel USH genes, we followed a candidate strategy, assuming that mutations in proteins interacting with this "USH network" may cause Usher syndrome as well. The DFNB31 gene encodes whirlin, a PDZ scaffold protein with expression in both hair cell stereocilia and retinal photoreceptor cells. Whirlin represents an excellent candidate for USH2 because it binds to Usherin (USH2A) and VLGR1b (USH2C). Genotyping of microsatellite markers specific for the DFNB31 gene locus on chromosome 9q32 was performed in a German USH2 family that had been excluded for all known USH loci. Patients showed common haplotypes. Sequence analysis of DFNB31 revealed compound heterozygosity for a nonsense mutation, p.Q103X, in exon 1, and a mutation in the splice donor site of exon 2, c.837+1G>A. DFNB31 mutations appear to be a rare cause of Usher syndrome, since no mutations were identified in an additional 96 USH2 patients. While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function. We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. Moreover, this is the first case of USH2 that is allelic to non-syndromic deafness.
UR - http://www.scopus.com/inward/record.url?scp=33947148611&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33947148611&partnerID=8YFLogxK
U2 - 10.1007/s00439-006-0304-0
DO - 10.1007/s00439-006-0304-0
M3 - Article
C2 - 17171570
AN - SCOPUS:33947148611
SN - 0340-6717
VL - 121
SP - 203
EP - 211
JO - Human genetics
JF - Human genetics
IS - 2
ER -