Molecular analysis of homocystinuria in Brazilian patients

Porto, Marianna Picarelli Ribeiro; Galdieri, Luciano; Pereira, Vanessa Gonçalves; Vergani, Naja; Rocha, José Cláudio; Micheletti, Cecília; Martins, Ana María; Perez, Ana Beatriz Alvarez; D’Almeida, Vânia

doi:10.1016/j.cccn.2005.05.030

Cited by 12 publications

(11 citation statements)

References 34 publications

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“…Recently, the mutation was also reported in two other Latin American countries, namely Venezuela (De Lucca and Casique 2004) and Brazil (Porto et al 2005). The highest prevalence was found in Colombia.…”

Section: Discussionmentioning

confidence: 76%

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

et al. 2006

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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

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Section: Discussionmentioning

confidence: 76%

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

et al. 2006

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“…In addition, betaine is administered to these patients, with folic acid and vitamin B12 supplementation in some cases. 5,7 It is estimated that the worldwide frequency of homocystinuria is 1 in 300 000, 3 while in the Philippines, only two patients have been registered since 1996. 8 Homocystinuria due to CBS deficiency is caused by mutations in the gene that encodes CBS.…”

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confidence: 99%

“…4,10 Alteration in CBS due to mutation results in the disruption of enzyme activity, which consequently leads to elevated homocysteine, a potentially toxic amino acid responsible for clinical manifestations observed in homocystinuric patients. 7,11 To date, 150 CBS mutations (http://cbs.lf1.cuni.cz/mutations.php) have been identified. Of these, 67% are missense mutations.…”

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confidence: 99%

Novel cystathionine β‐synthase gene mutations in a Filipino patient with classic homocystinuria

Silao

Fabella²,

Rama³

et al. 2015

Pediatrics International

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“…The molecular bases of HCU in Brazil are poorly characterized. In the only study published (Porto et al., ), CBS analysis performed by RFLP and SSCP is reported for 14 patients (11 unrelated) followed in a single medical center located in southeast Brazil. The common mutations p.Ile278Thr and p.Thr191Met were detected at a frequency of 13.6% each.…”

Section: Introductionmentioning

confidence: 99%

CBS mutations are good predictors for B6‐responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients

Poloni

Sperb‐Ludwig

Borsatto

et al. 2018

Molec Gen & Gen Med

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BackgroundClassical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine β‐synthase (CβS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU.Methods gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon‐intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT‐PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site‐directed mutagenesis.ResultsParental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty‐one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli‐expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT‐PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases.ConclusionsMost patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype–phenotype relationship was observed within families and for the four most common mutations.

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Molecular analysis of homocystinuria in Brazilian patients

Cited by 12 publications

References 34 publications

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

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

Novel cystathionine β‐synthase gene mutations in a Filipino patient with classic homocystinuria

CBS mutations are good predictors for B6‐responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients

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