A second gene for otosclerosis, OTSC2, maps to chromosome 7q34-36

Abstract

Otosclerosis due to abnormal bone homeostasis of the otic capsule is a frequent cause of hearing loss in adults. Usually, the hearing loss is conductive, resulting from fixation of the stapedial footplate, which prevents normal ossicular vibration in response to sound. An additional type of sensorineural hearing loss may be caused by otosclerotic damage to the cochlea. The etiology of the disease is unknown, and both environmental and genetic factors have been implicated. Autosomal dominant inheritance with reduced penetrance has been proposed, but large families are extremely rare. To elucidate the pathogenesis of the disease, identification of the responsible genes is essential. In this study, we completed linkage analysis in a Belgian family in which otosclerosis segregates as an autosomal dominant disease. After excluding linkage to a known locus on chromosome 15 (OTSC1), we found linkage on chromosome 7q, with a multipoint LOD score of 3.54. Analysis of key recombinant individuals maps this otosclerosis locus (OTSC2) to a 16-cM interval on chromosome 7q34-36 between markers D7S495 and D7S2426.

Figure 1

Pedigree of the Belgian family with autosomal dominant otosclerosis, showing the most likely haplotypes for the chromosome 7 markers. The haplotype linked to otosclerosis is boxed. Only family members whose DNA was analyzed are numbered. A question mark (?) inidicates family members with an atypical or limited hearing impairment; an asterisk (*) indicates persons with surgically confirmed otosclerosis; and an exclamation point (!) indicates the phenocopy (person III-19).

Figure 2

Localization of OTSC2 on chromosome 7q34-36. The black bar indicates the region on the Généthon genetic map (Dib et al. 1996) that contains the gene for otosclerosis. The distances between the markers are represented in centimorgans.