Haplotype analysis suggests that the two predominant mutations in Japanesepatients with holocarboxylase synthetase deficiency are founder mutations

Holocarboxylase synthetase (HCS) deficiency is a rare autosomal recessive d isorder of biotin metabolism. Including three new Japanese patients we diag nosed in this study, ten Japanese families have, so far, been accumulated. In these families, the mutations 237Leu > Pro (seven alleles) and 1067delG (five alleles) were predominant; 508Arg > Trp and 550Val > Met mutations we re identified in three families in the heterozygous form and in one patient in the homozygous form, respectively. To determine the origin of these mut ations, we identified new polymorphic microsatellite markers in the NCS gen e and analyzed the haplotypes of the patients. All the 237Leu > Pro and the 1067delG alleles were associated with haplotype 2-2 This finding is consis tent with the notion that these mutations are founder mutations in the Japa nese population. Three Japanese 508Arg > Trp alleles were associated with s everal haplotypes, including 2-3 and 1-4. The haplotype of a Taiwanese pati ent homozygous for the 508Arg > Trp mutation was 2-3/2-3, The haplotype of one Japanese patient homozygous for the 550Val > Met mutation was 1-4/1-4, whereas that of a Jewish patient with the same homozygous mutation was 2-3/ 2-3. Both mutations were associated with at least two haplotypes and were f ound in several ethnic groups. The changes 509Arg > Trp and 550Val > Met oc curred at CpG dinucleotide. The data suggest that these two mutations repre sent a mutational hot-spot.