Non-USH2A mutations in USH2 patients

Abstract

We have systematically analyzed the two known minor genes involved in Usher syndrome type 2, DFNB31 and GPR98, for mutations in a cohort of 31 patients not linked to USH2A. PDZD7, an Usher syndrome type 2 (USH2) related gene, was analyzed when indicated. We found that mutations in GPR98 contribute significantly to USH2. We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31, showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98, or DFNB31, showed that most of them had atypical features. In effect, these three genes account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis.

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.…”

Partial USH2A deletions contribute to Usher syndrome in Denmark

“…The remaining 35 patients had no function-affecting sequence variants identified before this investigation. The eight patients with two sequence variants in USH2A were included, as patients with three different function-affecting sequence variants located in two different genes 19,23 as well as patients with three different sequence variants located in the same gene, including USH2A, have been published previously. 15,24 The project was approved by the local ethics committee (H-3-2011-070) and carried out in accordance with the Declaration of Helsinki.…”

“…[12][13][14] Function-affecting variants in PCDH15 may not only lead to USH1, but also to autosomal recessive nonsyndromic profound hearing impairment (DFNB23). 12 Most patients with USH2, including patients from Denmark, have function-affecting variants in USH2A, [15][16][17][18][19] which is located on chromosome 1. Sequence variants in USH2A are also responsible for atypical Usher syndrome and recessive nonsyndromic RP.…”

Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

“…USH2 patients present with congenital moderate to severe hearing loss, retinitis pigmentosa (RP), and normal vestibular function. RP usually develops from the second decade onwards (Besnard et al, 2012; Chen et al, 2014). Early symptoms of RP include night blindness and loss of peripheral vision.…”

“…The PDZD7 mutation p.Arg56Profs*24 (c.166_167 insC) was suggested to be a retinal phenotype modifier in Usher syndrome in its heterozygous state. No biallelic mutations of PDZD7 were found in USH2 (Aparisi et al, 2014; Besnard et al, 2012). In this study, we did not find other functional candidate gene variants of classical Usher syndrome genes by targeted region capture and high throughput sequencing.…”