title: Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: high prevalence of T191M and absence of I278T or G307S.
abstract: Homocystinuria due to cystathionine beta-synthase (CBS) deficiency has been extensively studied, but to date, no spectrum of CBS mutations of Spanish homocystinuric patients has been reported. Here we present a mutation analysis of thirteen Spanish and three Portuguese unrelated homocystinuric patients. Ten mutations were found to account for the thirty-two mutant alleles and five of these (C275Y, L338P, S349N, R379Q, and L456P) are reported here for the first time. All five novel mutations were found to affect evolutionarily conserved residues suggesting that they may impair enzyme function. Interestingly, neither of the two common CBS mutations, I278T and G307S, was detected in this series, and no patient was found to respond to pyrodoxine. Enzyme activities in cultured fibroblasts from 10 of the patients were assayed, and they ranged from 0 to 13 % of controls analyzed in parallel. The T191M mutation (which has only ever been reported once before in a Spanish patient) accounted for 50% of the mutant alleles. Comparison of the clinical data of seven patients homozygous for T191M indicated that this genotype is a poor predictor of the phenotype. A common haplotype was identified in all the T191M chromosomes of Spanish origin, while a different one was present in the four T191M chromosomes from Portuguese patients.
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Urreizti
authors.forename: Susana
authors.initials: S
authors.lastname: Balcells
authors.forename: Marga
authors.initials: M
authors.lastname: Rodés
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.forename: Antonio
authors.initials: A
authors.lastname: Baldellou
authors.forename: María Luz
authors.initials: ML
authors.lastname: Couce
authors.forename: Carmen
authors.initials: C
authors.lastname: Muñoz
authors.forename: Jaume
authors.initials: J
authors.lastname: Campistol
authors.forename: Xavier
authors.initials: X
authors.lastname: Pintó
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Vilaseca
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006712:Homocystinuria / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007223:Infant; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D011174:Portugal / Q000453:epidemiology; D015995:Prevalence; D012694:Serine / Q000235:genetics; D013030:Spain / Q000453:epidemiology; D013912:Threonine / Q000235:genetics
chemical_list: D007532:Isoleucine; D013912:Threonine; D012694:Serine; D008715:Methionine; D003541:Cystathionine beta-Synthase; D005998:Glycine