Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria

Lee, Sook Jin; Lee, Dong Hwan; Yoo, Han Wook; Koo, Soo Kyung; Park, Eun Sook; Park, Joo Won; Lim, Hun Gil; Jung, Sung Chul

doi:10.1007/s10038-005-0312-2

Cited by 30 publications

(20 citation statements)

References 19 publications

(26 reference statements)

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“…The novel c.969G>A missense mutation, which encodes for the p.Trp323X termination, and the three non-synonymous recurrent mutations, which were identified in this study are located in the catalytic domain of the CBS (7). The recurrent c.770C>T (p.Thr257Met), c.1006C>T (p.Arg336Cys), and c.457G>A (p.Gly153Arg) mutations have been described previously (8)(9)(10)(11)(12)(13)(14)(15)(16). The c.770C>T (p.Thr257Met) mutation, which is found in the Sudanese family in this study, has been described in Italian and Spanish patients (15,17).…”

Section: Discussionsupporting

confidence: 58%

“…No genotypic or phenotypic data of these two patients were presented. The c.1006C>T (p.Arg336Cys) mutation has been described in patients of English (9), Australian (10), Portuguese (12), Korean (11), and Qatari Arab (13, 14) ancestries. In fact, the c.1006C>T (p.Arg336Cys) mutation was the most prevalent mutation described in the Qatari population with an allele frequency of 1% (14).…”

Section: Discussionmentioning

confidence: 99%

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Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria

et al. 2011

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Homocystinuria due to cystathionine beta synthase (CBS) deficiency results in elevated plasma homocysteine and methionine levels, which are associated with multiple organ pathologies, including vascular, respiratory, musculoskeletal, nervous, and ocular tissues. This autosomal recessive disorder is caused by homozygous or compound heterozygous mutations in the CBS gene encoding for the CBS. Although homocystinuria is observed in Arab and North African patients, their clinical presentations have not been described and molecular causes remained largely uninvestigated. In this study, we describe the clinical presentations of 22 homocystinuria patients from 13 Saudi Arabian families and 1 North African Sudanese family. Cardinal biochemical features of homocystinuria manifested in all patients, but heterogeneity of expression was observed for other associated phenotypes. One patient developed Legg-Calvé-Perthes disease that has not been previously described in homocystinuria. In the Saudi families, a novel nonsense mutation, p.Trp323X, and recurrent p.Arg336Cys and p.Gly153Arg mutations were identified in the CBS gene. The p.Trp323X mutation was found in 10 of the 13 unrelated Saudi families. In the Sudanese family, the p.Thr257Met mutation in the CBS gene, previously described in Italian and Spanish patients, was found. This study shows that the spectrum of CBS gene mutations in Saudi homocystinuria patients is quite different than the Arab patients from Qatar and Israel. This study is the only detailed phenotypic and genetic depiction of homocystinuria patients from Saudi Arabia and Sudan. The data are useful for diagnosis and management of Saudi patients.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria

et al. 2011

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“…The major cause of homocystinuria is mutation of the gene encoding CBS. More than 130 different CBS mutations have been reported, with the mutation C833T the most frequently observed (52,56). Deficiency of CBS activity results in elevated levels of tHcy and methionine in urine and plasma and decreased content of cystathionine and cysteine (32, 55,70).…”

Section: Cystathionine β-Synthase Deficiency and Liver Diseasementioning

confidence: 99%

Methionine Metabolism and Liver Disease

2008

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In the early 1930s, Banting and Best, the discoverers of insulin, found that choline could prevent the development of fatty liver disease (steatosis) in pancreatectomized dogs treated with insulin. Later work indicated that in rats and mice, diets deficient in labile methyl groups (choline, methionine, betaine, folate) produced fatty liver and that long-term administration of diets deficient in choline and methionine also caused hepatocellular carcinoma. These experiments not only linked steatosis and diabetes but also provided evidence, for the first time, of the importance of labile methyl group balance to maintain normal liver function. This conclusion is now amply supported by the observation of mice devoid of key enzymes of methionine and folate metabolism and in patients with severe deficiencies in these enzymes. Moreover, treatments with various methionine metabolites in experimental animal models of liver disease show hepatoprotective properties.

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“…The T353 M mutation has been described in Georgia, USA, where it was found exclusively in four African-American patients, and was associated with a B 6 -non-responsive phenotype [17]. It has also been found in Korean patients, all of them compound heterozygous [18].…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2011

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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.

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Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria

Cited by 30 publications

References 19 publications

Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria

Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria

Methionine Metabolism and Liver Disease

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

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