Fine mapping of the human biotinidase gene and haplotype analysis of five common mutations

Biotinidase deficiency is an autosomal recessive defect in the recycling of biotin that can lead to a variety of neurologic and cutaneous symptoms. Th e disease can be prevented or effectively treated with exogenous biotin. Th e biotinidase locus (BTD) has been maped to 3p25 by in situ hybridization. The gene has been cloned, the coding region sequenced, the genomic organiza tion determined, and a spectrum of mutations has been characterized in more than 90 individuals with profound or partial biotinidase deficiency, We ha ve conducted haplotype analysis of 10 consanguineous and 39 nonconsanguineo us probands from the United States and 8 consanguineous probands from Turke y to localize BTD with respect to polymorphic markers on 3p and to investig ate the origins of five common mutations. The inbred probands were homozygo us for overlapping regions of 3p ranging in size from 1.1 to 80 cM which we re flanked most narrowly by D3S1259 and D3S1293. Radiation hybrids and hapl otype analysis of markers within this region suggest that BTD is located wi thin a 0.1-cM region flanked by D3S3510 and D3S1286. The radiation hybrid d ata suggest that the BTD gene is oriented 5' to 3' between the centromere a nd the 3p telomere. Association studies indicate that the gene is closer to a third locus D3S3613 than D3S3510, two markers wh ich can not be resolved by existing linkage data. The BTD locus and D3S3613 must therefore lie bet ween D3S3510 and D3S1286. Comparison of haplotypes reveals evidence for pos sible founder effects for four of the five common mutations. Copyright (C) 1999 S. Karger AG, Basel.