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

Urreizti, Roser; Asteggiano, Carla; Bermúdez, Marta; Córdoba, Alfonso; Szlago, Marina; Grosso, Carola; Kremer, Raquel Dodelson de; Vilarinho, Laura; D’Almeida, Vânia; Martínez‐Pardo, Mercedes; Quintana, Luis Peña; Dalmau, Jaime; Bernal, Jaime; Briceño, Ignacio; Couce, María L.; Rodés, Margarita; Vilaseca, M. A.; Balcells, Susana; Grinberg, Daniel

doi:10.1007/s10038-006-0103-4

Cited by 4 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Homozygotes for this mutation may have B6-responsive homocystinuria with a mild phenotype or no symptoms [7;15], and strong ascertainment bias may well occur for them, although at the moment definitive proof of this possibility has not been presented. We consider that ascertainment bias is likely to be far less of a problem for B6-nonresponsive forms such as homozygosity for c.919G>A (p.G307S) (the mutation accounting for some 71% of those in Irish homocystinuria patients [16]), c.1006C>T (p.R336C) [17], the mutation found in the Qatari population in the homozygous state in 1:2100 newborns among 12,603 screened [18], or c.572C>T (p.T191M), the mutation highly prevalent in Spain, Portugal, and South America [19]. …”

Section: Ascertainment Biasmentioning

confidence: 99%

A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency

Skovby

Gaustadnes

Mudd

2010

Molecular Genetics and Metabolism

130

View full text Add to dashboard Cite

We review the evidence that in Denmark and probably certain other European countries the number of individuals identified with homocystinuria due to homozygosity for the widespread c.833T>C (p.I278T) mutation in the gene that encodes cystathionine β-synthase (CBS) falls far short of the number of such individuals expected on the basis of the heterozygote frequency for this mutation found by molecular screening. We conclude that the predominant portion of such homozygotes may be clinically unaffected, or may be ascertained for thromboembolic events occurring no sooner than the third decade of life. If so, there was significant ascertainment bias in the time-to-event curves previously published describing the natural history of untreated CBS deficiency [Mudd et al, 1985] and these curves should be used with care.

show abstract

Section: Ascertainment Biasmentioning

confidence: 99%

A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency

Skovby

Gaustadnes

Mudd

2010

Molecular Genetics and Metabolism

130

View full text Add to dashboard Cite

show abstract

“…These findings appear to reflect the greater genetic heterogeneity of Brazil as compared with other Latin American countries and, possibly, the more limited contribution of Spanish immigration to Brazil (IBGE, ; Kehdy et al., ; Pena et al., ; Resque et al., ). Wide phenotypic variability has been observed for this mutation, with mild to severe phenotypes and pyridoxine responsiveness ranging from partial to absent (Kraus, ; Urreizti et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…However, taken together, the four most prevalent mutations (p.Ile278Thr, p.Thr191Met, p.Gly307Ser, and p.Arg336Cys) account for more than half of all HCU alleles worldwide (Kraus, ). While the first of these mutations is panethnic, the other three follow rather well‐demarcated geographic and ethnic distributions (Cozar et al., ; El‐Said et al., ; Gallagher et al., ; Porto et al., ; Shih et al., ; Urreizti et al., ). The molecular bases of HCU in Brazil are poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

“…It is also reported that homozygotes for this mutation may have a higher risk of developing thromboembolism instead of other HCU symptoms (Magner et al., ; Skovby et al., ). Patients carrying the Latin/Iberian p.Thr191Met mutation are usually nonresponsive to pyridoxine, but a great variability of severity and clinical symptoms can be observed (Cozar et al., ; Urreizti et al., ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

“…The c.919G[A transition (p.G307S) mutation is also prevalent, mainly in alleles from patients of Celtic origin [12], and it is related to a more severe clinical phenotype. The third most prevalent mutation, c.572C[T transition (p.T191 M), is very common in the Iberian peninsula and Latin American countries [13], has been reported to be B 6 -non-responsive, and homozygotes seem to have a low prevalence of vascular disease.…”

Section: Discussionmentioning

confidence: 99%

Classical familial homocystinuria in an adult presenting as an isolated lens subluxation

et al. 2011

View full text Add to dashboard Cite

To report a case of late diagnosis of a classical familial homocystinuria based on an ophthalmologic examination. A 35-year-old male with Marfan-like phenotype complained of a progressive increase of myopia during the previous 2 years. Ophthalmologic exploration showed a bilateral subluxation of the lens with inferior and nasal displacement. Biochemical study detected a profile of increased amino acid levels (homocysteinemia) consistent with suspected homocystinuria. Vascular and skeletal studies ruled out Marfan syndrome. Response to treatment demonstrated B(6)-non-responsive homocystinuria. Molecular study showed compound heterozygous T353 N and D444 N mutations of the cystathionine beta-synthase (CBS) gene, and also a C667T homozygous mutation of the methylenetetrahydrofolate-reductase (MTHFR) gene. Family study showed classical homocystinuria in his father and sister, although they did not present any systemic or ocular features of the disease. Homocystinuria is a metabolic disease usually presenting at an early age as vascular, skeletal and neuropsychiatric abnormalities, as well as ectopia lentis. Our case is atypical because of the absence of thromboembolism and the mild phenotype, in spite of being B(6)-non-responsive, and the association of a rare compound heterozygous mutation of the CBS gene and also an homozygous mutation of the MTHFR gene. It is necessary to rule out homocystinuria in patients with ectopia lentis, even in the absence of systemic symptoms.

show abstract

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

Cited by 4 publications

References 0 publications

A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency

A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency

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

Classical familial homocystinuria in an adult presenting as an isolated lens subluxation

Contact Info

Product

Resources

About