A Meniere's disease gene linked to chromosome 12p12.3

Abstract

Meniere's disease (MD) is characterized by spontaneous attacks of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. The majority of patients with MD appear sporadic but 5%-13% of the cases have a family history for the disease. The cause of both the sporadic and inherited forms of MD remains unclear despite a number of candidate genes defined from their association with hearing loss. We have performed a genome wide linkage scan on a large Swedish family segregating MD in five generations. Five candidate regions with a lod score of >1 were identified. Two additional families with autosomal dominant MD were analyzed for linkage to these regions and a cumulative Z(max) of 3.46 was obtained for a single region on chromosome 12p. In two of the three families, a shared haplotype was found to extend over 1.7 Mb which suggests a common ancestral origin. Within this region, a single recombination event restricts the candidate region to 463 kb.

Familiar Meniere's disease restricted to 1.48 Mb on chromosome 12p12.3 by allelic and haplotype association

“…Two genes are positioned in the refined susceptibility locus, the RERG/RAS-like gene (RERGL), and part of the previously sequenced PIK3C2G gene. 28 RERGL binds to GDP/GTP and may possess intrinsic GTPase activity, making it another likely candidate for MD. 34 However, none of these genes show any sequence alterations in the coding sequences associated to MD.…”

“…Expansion of the haplotypes identified two overlapping haplotypes spanning seven markers (D12S363 to TC33, P excess ¼0.357, P¼0.011 and TA35 to GT11, P excess ¼0.333, Po0.01) each present in 40% of the MD families. Furthermore, 33% of the families, including the two families previously described, 28 share a haplotype comprising 11 markers (D12S363 to GT11, P excess ¼0.379, Po0.01; Table 2). Considering both single marker and haplotype associations, the region spanning 1.48 Mb between the markers D12S373 and GT27 is strongly associated with MD in the Swedish population.…”

“…28 Altogether, 24 affected and 14 unaffected individuals from the families segregating FMD were genotyped. Furthermore, a control group consisting of 31 ethnically matched family trios without any history of MD or partial MD symptoms were genotyped.…”

“…28 To refine the region, we genotyped an additional 13 markers including six markers selected from public databases (NCBI, build 36.3) and seven novel polymorphic repeats. The previously reported shared haplotype in two of our families could also be confirmed and using the additional markers this shared haplotype now spans 1.6 Mb between marker D12S1630 and GT27.…”

“…27 We have previously identified a candidate region for familial MD (FMD) on chromosome 12p12.3 from linkage analysis using three large Swedish families segregating the disease. 28 Furthermore, affected individuals in two of the families share a single haplotype spanning the linked region, suggesting a possible ancestral mutation. To further investigate the chromosome 12p12 region in FMD, we performed a genetic analysis in 15 multiplex families segregating MD in at least two individuals.…”