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

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.

Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome

“…In addition, while many patients with Usher syndrome have significant vestibular dysfunction, 40 it is unclear whether patients with whirlin mutations (DFNB31 or Usher 2D) have vestibular deficits. 9,10,21,[41][42][43] None of the studies that reported on the phenotypes of these patients included detailed vestibular function tests. Therefore, additional studies are required to investigate the vestibular function in patients with whirlin mutations in order to gauge the potential therapeutic benefits of whirlin gene therapy on balance function in these patients.…”

“…4,7 WHRN encodes a scaffolding protein called whirlin, which is required for normal hair cell stereocilia elongation. 8 Mutations in the WHRN gene can cause Usher syndrome type 2D (OMIM 611383), 9 as well as the non-syndromic autosomal recessive hearing loss DFNB31 (OMIM 607084). 10 The whirler mouse (Whrn wi/wi ) does not produce functional whirlin proteins in the inner ear, 11 resulting in abnormally short stereocilia in cochlear and vestibular hair cells.…”

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

“…Whirlin binds to the protein encoded by USH2A (18), a gene associated with both Usher syndrome type II (ARRP accompanied by hearing loss) and nonsyndromic ARRP (19). Whereas mutations in DFNB31 have been reported as rare causes of Usher syndrome type II (20,21), no DNA changes in its sequence have yet been associated with nonsyndromic ARRP. However, at the age of 66, the past medical history of this patient was significant for only hyperlipidemia and she did not report any hearing loss.…”

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

“…Whirlin contains three highly-conserved PDZ domains, mutations in which cause the 'whirler' phenotype in mice and prelingual-onset nonsyndromic deafness in humans, 36 including some types of Usher syndrome. 37 Like nucleoredoxin, the Usher protein complex is an effector of b-catenin, and also affects neuronal morphogenesis and structural plasticity. 38 Usher syndrome can cause central nervous system structural changes 39 and psychosis, 40 and there is one report of increased incidence of bipolar disorder among adults with prelingual-onset nonsyndromic deafness, 41 but it is not known if any of those patients carried the 'whirler' mutation.…”