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 individuals 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.

Figure 1

USH1K families PKDF231 and PKDF608 and their representative audiograms. (a) Chromosome 10 haplotypes in family PKDF231. Filled symbols represent deaf individuals. The USH1J-linked haplotype is boxed. The STR markers and physical map positions in megabases (Mb, February 2009 human reference sequence GRCh37, hg19) are shown on the left of the pedigree. Haplotype analysis of PKDF231 shows a linkage region of 20.20 Mb delimited by markers D10S1780 (35.89 Mb) and D10S546 (56.09 Mb). Affected individuals V:2, V:3, V:4, V:5 and V:7 provided distal meiotic breakpoint at D10S546 (56.09 Mb), while the unaffected individual V:6 provided the proximal recombination at D10S1780 (35.89 Mb). In family PKDF608 affected individual V:18 provided the proximal meiotic breakpoint at marker D10S1780 (35.89 Mb). The distal breakpoint at marker D10S1652 (64.31 Mb) was provided by affected individual V:29 (data not shown). (b) Pure tone air and bone conduction thresholds for family PKDF231 V:7 (26 yo male), and family PKDF608 V:20 (45 yo male) revealed profound, bilateral, sensorineural hearing loss. Right ear air conduction: O; Left ear air conduction: X; Right ear bone conduction: >; Left ear bone conduction: <; ↓ indicates the threshold level beyond the measurable range.

Figure 2

USH1K linkage intervals in families PKDF231 and PKDF608 on human chromosome 10p11.21-q21.1. STR markers are represented by filled circles. The sex averaged recombination positions in cM are indicated for STR markers. Candidate genes in the USH1K interval were identified from the UCSC Human Genome Browser February 2009 assembly (http://genome.ucsc.edu/). Candidate genes expressed in the inner ear are underlined. Previously reported deafness locus DFNB33 interval and USH1F/DFNB23 causing gene PCDH15 is also shown.