USH1K, a novel locus for type I Usher syndrome, maps to chromosome 10p11.21–q21.1

Abstract

We ascertained two large Pakistani consanguineous families (PKDF231 and PKDF608) segregating profound hearing loss, vestibular dysfunction, and retinitis pigmentosa, the defining features of Usher syndrome type 1 (USH1). To date seven USH1 loci have been reported. Here, we map a novel locus, USH1K, on chromosome 10p11.21-q21.1. In family PKDF231 we performed a genome-wide linkage screen and found a region of homozygosity shared among the affected individual at chromosome 10p11.21-q21.1. Meiotic recombination events in family PKDF231 define a critical interval of 11.74 cM (20.20 Mb) bounded by markers D10S1780 (63.83 cM) and D10S546 (75.57 cM). Affected individuals of family PKDF608 were also homozygous for chromosome 10p11-21-q21.1 linked STR markers. Of the 85 genes within the linkage interval, PCDH15, GJD4, FZD4, RET, and LRRC18 were sequenced in both families, but no potential pathogenic mutation was identified. The USH1K locus overlaps the non-syndromic deafness locus DFNB33 raising the possibility that the two disorders may be caused by allelic mutations.

The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex

“…Depending on which component of the Usher complex is mutated, patients are classified as having a different variant of USH1 (for example patients with deleterious genetic defects in Myo7a suffer from USH1B). Of note, the causative genes for three USH1 subtypes (USH1E, USH1K and USH1H) still have not been identified, suggesting that more Usher complex components may remain to be discovered (17)(18)(19). A similar situation is seen with the IMAC; structure-function studies of this complex clearly point towards the idea that the full interactome is not yet known (5,20,21).…”

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

“…2 To date, there are 13 loci and 10 genes known to be involved in the three clinical types of Usher syndrome. [3][4][5][6] Mutations in six of these genes, MYO7A, 7-10 CDH23, 11,12 PCDH15, 13,14 WHRN, 15,16 SANS 17 and CIB2, 4 can lead to either Usher syndrome or autosomal recessive NSHI (arNSHI). Mutations in USH2A can lead to either Usher syndrome or nonsyndromic retinitis pigmentosa.…”

Usher proteins in inner ear structure and function

“…Clinically, USH is classified into three presenting subtypes, type I, II, and III based on the severity and age of onset (2). USH type I (USH1) is the most genetically heterogeneous: 14 loci have been mapped for USH, and genes for 11 have been identified (19,27,40). Although mutations in each of these genes cause USH, certain missense mutations cause only deafness or only retinitis pigmentosa (2,27,38,40).…”