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 β-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.

The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America

“…The phenotypic features of some of these patients have been described previously (Urreizti et al 2003). The lack of response to treatment with vitamin B 6 was the only feature present in all of these patients.…”

“…Analysis of the CBS 844ins68 polymorphism was carried out using primers CBS_8F and CBS_8R (Table 1) to yield a product of 596 bp (if wild-type) and of 664 bp (if the insertion was present). The analyses of the polymorphisms c.699C >T and c.1080C >T of CBS and c.677C>T of MTHFR, as well as the STR D21S1411 (GenBank L17803), were performed as previously described (Urreizti et al 2003).…”

“…On the other hand, a c.919G>A transition (p.G307S) is related to a more severe clinical phenotype and has been detected mainly in alleles from homocystinuric patients of Celtic origin, representing nearly 70% of the homocystinuric alleles in Ireland (Gallagher et al 1995). We previously reported the third most prevalent mutation, a c.572C>T transition (p.T191M), which is very common in the Iberian Peninsula, representing 50% of all Spanish homocystinuric alleles (Urreizti et al 2003). Patients homozygous for the p.T191M mutation were found to be B 6 -nonresponders.…”

Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations

“…Worldwide, five such mutations (p.I278T, p.T191M, p.G307S, and IVS11-2A<C) are particularly prevalent and together account for approximately 48% of the alleles characterized in patients thus far. In particular, p.T191M was found to be highly prevalent in the Iberian Peninsula [Urreizti et al, 2003]. The remaining mutations in the CBS database are mostly private.…”

Newborn Screening for Homocystinuria Revealed a High Frequency of MAT I/III Deficiency in Iberian Peninsula

“…On the other hand, mutation p.T191M, a pyridoxine nonresponsive mutation, seems to be prevalent in this region (Urreizti et al 2003;Urreitzi et al 2006). Mutation p.G307S is also a frequent pyridoxine nonresponsive mutation in northern Europe (Gallagher et al 1995) and is probably of Celtic origin.…”