USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22‐23

Abstract

Usher syndrome (USH) is a hereditary disorder associated with sensorineural hearing impairment, progressive loss of vision attributable to retinitis pigmentosa (RP) and variable vestibular function. Three clinical types have been described with type I (USH1) being the most severe. To date, six USH1 loci have been reported. We ascertained two large Pakistani consanguineous families segregating profound hearing loss, vestibular dysfunction, and RP, the defining features of USH1. In these families, we excluded linkage of USH to the 11 known USH loci and subsequently performed a genome-wide linkage screen. We found a novel USH1 locus designated USH1H that mapped to chromosome 15q22-23 in a 4.92-cM interval. This locus overlaps the non-syndromic deafness locus DFNB48 raising the possibility that the two disorders may be caused by allelic mutations.

Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

“…Besides that, vestibular dysfunction, later confirmed by ENG, was suspected as there was a delayed onset of ambulation. 35 The DFNB48 phenotype found in three of the four families reported in the present study is consistent with the previously described DFNB48 phenotype, 4,36 severe to profound, prelingual bilateral HI without signs of retinitis pigmentosa and vestibular dysfunction. However, the HI in family W09-1575 with the recurrent homozygous variant, is less severe.…”

“…As electroretinography could not be performed, we cannot exclude an early stage of retinitis pigmentosa in these individuals. However, classical USH1J as diagnosed in the USH1J family with the c.192G4C variant in the homozygous state 4,35 is excluded in the present families because of the absence of vestibular areflexia, and for family W06-0987, in addition, because of lack of symptoms of retinal degeneration at 24 years of age. 2 The difference in phenotypic effect of the c.192G4C (p.(Glu64Asp)) and c.196C4T (p. (Arg66Trp)) variants in CIB2 might be the result of a larger negative effect of the former mutation because of loss of a salt bridge between residues Arg33 and Glu64, which is formed in the absence of integrin.…”

SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis

“…13 The NCEMB study population is a robust model for genotypic studies of non-syndromic and syndromic deafness phenotypes in Pakistan. 8,[14][15][16][17][18][19] The goal of our study was to define the identities, frequencies and origins of SLC26A4 pathogenic variants in a much larger cohort of 775 Pakistani families segregating recessive severe-toprofound deafness with or without goiter. We show that SLC26A4 mutations are a common cause of genetic deafness among Pakistanis and their distinctive spectrum lends itself to hierarchical detection strategies.…”

Association of Whirlin with Cav1.3 (α1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network

“…1 To date, the affected genes have been identified for 9 of the 12 described Usher loci. [2][3][4][5][6][7][8][9][10] Besides being causative of Usher syndrome, mutations in the Usher genes MYO7A, USH1C, CDH23, PCDH15, and DFNB31 are also associated with nonsyndromic hearing loss. 2,6 -10 In addition, mutations in the USH2A gene can lead to nonsyndromic autosomal recessive RP.…”