GENETIC-HETEROGENEITY OF USHER SYNDROME TYPE-1 IN FRENCH FAMILIES

Usher syndrome type 1 (US1) is an autosomal recessive disease characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Three localizations have been described in US1: USH1A, 14q32; USH1B, 11q13.5; and USH1C, 11p15. Studying a series of 33 affected individuals belonging to 20 US1 pedigrees of French ancestry, we found that none of the three localizations accounted for all US1 families in our series (Z(max) = 1.48 at theta = 0.10; Z(max) = 1.45 at theta = 0.10; and Z(max) = 0.36 at theta = 0.20 for probes MLJ14, Zd5, and Mfd58, respectively, at loci D14S13, D11S527, and D11S419, respectively). However, when our sample was split into two groups according to the geographic origin of the probands' grandparents, we were able to confirm the presence of a gene for US1 on chromosome 14q32 (USH1A) in 9 families originating from the Poitou region in Western France (Department of Deux-Sevres; Z(max) = 4.46 at theta = 0 for probe MWJ14 at the D14S13 locus, Morton likelihood ratio test, P < 0.01). Moreover, we refined the genetic mapping of USH1A by showing that the disease gene maps to the D14S13 locus, within the genetic interval defined by loci D14S78 and D14S250 (location score in log base 10 = 4.90). Consistent with this, nonsignificant lod score values for linkage to either USH1B or USH1C were found in this group. With regard to US1 families of other geographic origin (Normandy and Northern France, 11 families), nonsignificant lod scores for linkage to chromosome 11q13.5 were observed (Z(max) = 1.83 and Z(max) = 2.23 at theta = 10 for probes Zd5 and AFM185ya1, respectively, at loci D11S527 and D11S916, respectively). However, the HOMOG test suggested that USH1B might account for the disease in 9/11 families in our series (families 10-19), the latter two families possibly being accounted for by USH1C (maximum likelihood for heterogeneity = 7.91 in In L; heterogeneity versus homogeneity, P = 0.01; heterogeneity versus nonlinkage, P < 0.01). The present study supports the view that Usher syndrome type 1 is a genetically heterogeneous condition that is caused by at least three genes and possibly many more. (C) 1994 Academic Press, Inc.