title: Mutations in the holocarboxylase synthetase gene HLCS.
abstract: Holocarboxylase synthetase (HLCS) deficiency is an autosomal recessive disorder. HLCS is an enzyme that catalyzes biotin incorporation into carboxylases and histones. Since the first report of the cDNA sequence, 30 mutations in the HLCS gene have been reported. Mutations occur throughout the entire coding region except exons 6 and 10. The types of mutations are one single amino acid deletion, five single nucleotide insertions/deletions, 22 missense mutations, and two nonsense mutations. The only intronic mutation identified thus far is c.1519+5G>A (also designated IVS10+5G>A), which causes a splice error. Several lines of evidence suggest that c.1519+5G>A is a founder mutation in Scandinavian patients. Prevalence of this mutation is about 10 times higher in the Faroe Islands than in the rest of the world. The mutations p.L237P and c.780delG are predominant only in Japanese patients. These are probably founder mutations in this population. Mutations p.R508W and p.V550M are identified in several ethic groups and accompanied with various haplotypes, suggesting that these are recurrent mutations. There is a good relationship between clinical biotin responsiveness and the residual activity of HLCS. A combination of a null mutation and a point mutation that shows less than a few percent of the normal activity results in neonatal onset. Patients who have mutant HLCS with higher residual activity develop symptom after the neonatal period and show a good clinical response to biotin therapy.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. ysuzuki@faculty.chiba-u.jp
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
mesh_terms: D001710:Biotin / Q000627:therapeutic use; D019731:Carbon-Nitrogen Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D001710:Biotin; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases