Cystathionine ?-synthase mutations in homocystinuria

Kraus, Jan P.; Jánošík, Miroslav; Kožich, Viktor; Mandell, Roseann; Shih, Vivian E.; Sperandeo, Maria Pia; Sebastio, Gianfranco; Franchis, R. de; Andria, Generoso; Kluijtmans, Leo A. J.; Blom, Henk J.; Boers, G.H.J.; Gordon, R. D.; Kamoun, P.; Tsai, Michael Y.; Kruger, Warren D.; Koch, Hans Georg; Ohura, Toshihiro; Gaustadnes, Mette

doi:10.1002/(sici)1098-1004(1999)13:5<362::aid-humu4>3.0.co;2-k

Cited by 270 publications

(158 citation statements)

References 31 publications

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“…Clinical and biochemical data were provided by the patients' physicians. Disease severity and B6 responsiveness were assessed by each physician according to criteria described in Kraus et al [1999]. Our research was conducted in accordance with the tenets of the Declaration of Helsinki.…”

Section: Patientsmentioning

confidence: 99%

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Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

et al. 2003

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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.

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Section: Patientsmentioning

confidence: 99%

“…Sequence reactions were performed using BigDye Terminator Cycle Sequencing v 2.0, (Abi Prism, Applied Biosystems) and they were analyzed with an ABI PRISM 3700 DNA Analyzer from Applied Biosystems. Kraus et al [1999].…”

Section: Scanning For Mutations Of the Cbs Genementioning

confidence: 99%

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

et al. 2003

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“…Several pieces of evidence support this view. It was shown previously that homozygosity and compound heterozygosity for the c.833T>C mutation is almost always associated with pyridoxine responsiveness (Kraus et al, 1999), and that pyridoxine responders exhibit milder phenotype with a later onset of disease and later age of diagnosis (Mudd et al, 1985). Detection of numerous adult homocystinuric patients with a mild phenotype and pyridoxine responsiveness was reported recently after total plasma homocysteine determination became easily available (Cruysberg et al, 1996;Gaustadnes et al, 2000a;Gaustadnes et al, 2000b).…”

Section: Discussionmentioning

confidence: 99%

“…1:20,500, than expected . Homocystinuria can be caused by homozygosity or compound heterozygosity for any of over a hundred pathogenic alleles (Kraus et al, 1999;Mudd et al, 2001). In Caucasians the most common pathogenic allele is the c.833T>C, which is associated with pyridoxine responsiveness.…”

Section: Introductionmentioning

confidence: 99%

Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

Sokolová¹,

Janošı́ková²,

Terwilliger³

et al. 2001

Hum. Mutat.

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Recent reports suggested that homocystinuria due to cystathionine beta-synthase (CBS) deficiency is a more common inborn error of metabolism than originally thought. In this study we compared the prevalence of homocystinuric alleles ascertained by two different approaches. First, the incidence of homocystinuria estimated by selective biochemical screening in the Czech and Slovak Republics was 1:349,000 (95% CI 1:208,000-1:641,000). The two most common pathogenic mutant alleles found subsequently in these patients, IVS11-2A>C and c.833T>C, had a calculated population prevalence of 0.00042 (95% CI 0.00031-0.00055) and 0.00018 (95% CI 0.00013-0.00023), respectively. Second, to examine the possible negative detection bias of mildly affected patients we determined the prevalence of these two pathogenic mutations in a sample of 1284 unselected newborns. Indeed, the observed prevalence of the c.833T>C allele (0.00195, 95% CI 0.00063-0.00454) was 11x higher than in the previous group suggesting that many homozygotes for the c.833T>C had not been diagnosed by selective biochemical screening. The IVS11-2A>C allele was not detected among 2,568 newborn CBS alleles. The estimated incidence of homocystinuria of 1:83,000, calculated in a combined model, suggests that selective biochemical screening may ascertain only ~25% of all homocystinuric patients. In conclusion, homocystinuria in Central Europe may be sufficiently common to consider sensitive newborn screening programs for this disease.

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“…In humans, most pathogenic mutations are missense mutations within the CBS gene (Kraus et al, 1999). Further experiments remain to be evaluated; including potentials of alternative AAV serotypes, not AAV2 and the efficacy of rAAV delivered prenatally.…”

Section: Discussionmentioning

confidence: 99%

Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria

Park

Kruger³

et al. 2006

Exp Mol Med

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Homocystinuria is a metabolic disorder caused by a deficiency of cystathionine β-synthase (CBS). The major clinical symptoms of this disease are mental retardation, lens dislocation, vascular disease with life-threatening thromboembolisms, and skeletal deformities. The major treatments for CBS deficiency include pharmacologic doses of pyridoxine or dietary restriction of methionine. There is currently no effective long-term treatment to lower the elevated plasma levels of homocysteine. However, gene therapy could be an effective novel approach for the treatment of homocystinuria. A recombinant adenoassociated virus vector carrying human CBS cDNA (rAAV-hCBS) was constructed and administered to CBS -/-mice by intramuscular (IM) and intraperitoneal (IP) injections. Serum homocysteine concentrations significantly decreased in treated mice compared with age-matched controls two weeks after treatment. The treated CBS -/-mice had life spans 3-7 days longer compared with untreated CBS -/-mice. In CBS -/-mice treated with rAAV-hCBS via IP injection, the vector was detected in all organs examined including liver, spleen, and kidney, and CBS gene expression was observed by immunohistochemical staining in the liver. These results indicate the efficacy of gene delivery and demonstrate the possibility of gene therapy mediated by AAV gene transfer in this mouse model of homocystinuria.

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Cystathionine ?-synthase mutations in homocystinuria

Cited by 270 publications

References 31 publications

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria

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