Human Genetics

, Volume 121, Issue 2, pp 203–211

A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss

  • Inga Ebermann
  • Hendrik P. N. Scholl
  • Peter Charbel Issa
  • Elvir Becirovic
  • Jürgen Lamprecht
  • Bernhard Jurklies
  • José M. Millán
  • Elena Aller
  • Diana Mitter
  • Hanno Bolz
Original Investigation

DOI: 10.1007/s00439-006-0304-0

Cite this article as:
Ebermann, I., Scholl, H.P.N., Charbel Issa, P. et al. Hum Genet (2007) 121: 203. doi:10.1007/s00439-006-0304-0

Abstract

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.

Supplementary material

439_2006_304_MOESM1_ESM.doc (26 kb)
Table S1 Primers for genomic amplification of DFNB31 exons. The length of coding sequences and the size of the genomic amplicons is given (DOC 26 kb)

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Inga Ebermann
    • 1
  • Hendrik P. N. Scholl
    • 2
  • Peter Charbel Issa
    • 2
  • Elvir Becirovic
    • 1
  • Jürgen Lamprecht
    • 3
  • Bernhard Jurklies
    • 4
  • José M. Millán
    • 5
  • Elena Aller
    • 5
  • Diana Mitter
    • 6
  • Hanno Bolz
    • 1
  1. 1.Institute of Human GeneticsUniversity Hospital of CologneCologneGermany
  2. 2.Department of OphthalmologyUniversity of BonnBonnGermany
  3. 3.Department of ENTAlfried Krupp HospitalEssenGermany
  4. 4.Department of OphthalmologyUniversity Hospital of EssenEssenGermany
  5. 5.Unidad de GenéticaHospital La FeValenciaSpain
  6. 6.Institute of Human GeneticsUniversity Hospital of EssenEssenGermany