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

Abstract

Classical homocystinuria is due to cystathionine b-synthase (CBS) deficiency. More than 130 mutations, which differ in prevalence and severity, have been described at the CBS gene. Mutation p.I278T is very prevalent, has been found in all European countries where it has been looked for with the exception of the Iberian peninsula, and is known to respond to vitamin B 6 . On the other hand, mutation p.T191M is prevalent in Spain and Portugal and does not respond to B 6 . We analysed 30 pedigrees from Spain, Portugal, Colombia and Argentina, segregating for homocystinuria. The p.T191M mutation was detected in patients from all four countries and was particularly prevalent in Colombia. The number of p.T191M alleles described in this study, together with those previously published, is 71. The prevalence of p.T191M among CBS mutant alleles in the different countries was: 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina and 0.14 in Brazil. Haplotype analyses suggested a double origin for this mutation. No genotype-phenotype correlation other than the B 6 -nonresponsiveness could be established for the p.T191M mutation. Additionally, three new mutations, p.M173V, p.I429del and c.69_70+8del10, were found. The

Vascular and connective tissue features in 5 Italian patients with homocystinuria

“…This mutation, however, is not present in 50 South American [14] and 300 Italian controls (this report).…”

“…Patient #3 leads another mutation, carried by an Argentinean patient [14], recently published on-line that consists in a deletion of three nucleotides (c.1286_1288delTCA) causing a deletion of amino acid Ile429, the mutation being positioned in a non conserved domain. This mutation, however, is not present in 50 South American [14] and 300 Italian controls (this report).…”

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

“…These patients were already referred to in previous publications (Urreitzi et al 2006;Couce et al 2008Couce et al , 2013.…”

“…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.…”

Discovery of a novel cystathionine-beta-synthase mutation and diagnosis of homocystinuria by whole exome sequencing in a family from rural Honduras

“…To date over 160 pathogenic variants have been identified in the CBS gene (http://cbs.lf1.cuni.cz/mutations.php). Common variants display distinct regional and ethnic distributions, including c.833T>C (p.Ile287Thr) in eastern Europe [6] , c.919G>A (p.Gly307Ser) in Ireland [7] , and c.572C>T (p.Thr191Met) in Iberian Peninsular and Colombian populations [8] and are commonly targeted in screening of at-risk populations. Additional rare or novel CBS mutations are typically isolated to individual communities and identified through sequencing following a complete clinical workup [9] .…”