Molecular basis of phenotype expression in homocystinuria

Kraus, Jan P.

doi:10.1007/bf00711354

Cited by 103 publications

(52 citation statements)

References 14 publications

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“…No well-defined correlation between genotype and phenotype has been established in CBS deficiency. 9,27 However, it appears that homozygosity for the 919G3 A (G307S) mutation correlates with pyridoxine nonresponsiveness, 28 whereas homozygosity for the 833T3 C mutation correlates with pyridoxine responsiveness, in agreement with treatment results in our study family. 10,19 Yet exceptions from this rule exist.…”

Section: Pyridoxine Responsivenesssupporting

confidence: 89%

Familial Thrombophilia Associated With Homozygosity for the Cystathionine β-Synthase 833T→C Mutation

Gaustadnes

Rüdiger

Rasmussen

et al. 2000

ATVB

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Abstract-Severe hyperhomocysteinemia due to cystathionine ␤-synthase (CBS) deficiency is a strong risk factor for premature cardiovascular disease. Among untreated patients, Ϸ50% have suffered a thromboembolic event by 30 years of age. We report on 3 sisters with severe hyperhomocysteinemia due to homozygosity for the CBS 833T3 C mutation. These patients, who displayed no other known thrombophilic predisposition, had suffered single or multiple venous thrombosis before CBS deficiency was diagnosed relatively late in life. In this family, homozygosity for the 833T3 C mutation was associated with a mild phenotype with respect to other sequelae of CBS deficiency. Consequently, our results indicate that most cases with this genotype may remain undiagnosed. Investigated family members heterozygous for the 833T3 C mutation displayed normal total homocysteine in plasma (tHcy) levels, even when they were homozygous for the methylenetetrahydrofolate reductase 677C3 T polymorphism. The prevalence of homozygosity for the 833T3 C mutation has previously been estimated at no less than 1:20 500 in our population. Because a reduction of the severely elevated levels of tHcy in CBS deficiency reduces cardiovascular risk and because homozygosity for the 833T3 C mutation is more prevalent than previously thought, our results emphasize the importance of measuring tHcy routinely in thrombophilia screening. Key Words: venous thrombosis Ⅲ severe hyperhomocysteinemia Ⅲ cystathionine ␤-synthase deficiency Ⅲ family history Ⅲ mutation analysis A n elevated plasma level of homocysteine is an independent risk factor for arterial as well as venous thrombosis. 1,2 Mild or moderate hyperhomocysteinemia (an increased level of total homocysteine in plasma [tHcy] up to 30 mol/L and 30 to 100 mol/L, respectively) may result from a relative deficiency of folic acid, vitamin B 12 , or vitamin B 6 3 or from homozygosity for a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene (677C3 T). 4 Severe hyperhomocysteinemia (tHcy Ͼ100 mol/L) is most often caused by cystathionine ␤-synthase (CBS, EC 4.2.1.22) deficiency. 5 This autosomal recessive disease is the most common inborn error of sulfur amino acid metabolism, with an estimated incidence of Ϸ1:200 000 worldwide, ranging from 1:20 500 to 1:1 000 000 in different populations. 6,7 The clinical manifestations include premature atherosclerosis and early thromboembolism, ectopia lentis, mental retardation, other neuropsychiatric manifestations, and skeletal abnormalities, including osteoporosis. Vascular complications constitute the major cause of death. 5 Overall, 50% of patients with untreated CBS deficiency have suffered a thromboembolic event by 30 years of age. 8 Vascular occlusion can occur in any vessel at any age, with the majority of such occurrences involving peripheral veins (51%) and complicated by pulmonary embolism in one fourth of those cases. 5 Because most countries do not systematically screen newborns for homocystinuria, the majority of cases of CBS deficiency ...

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Section: Pyridoxine Responsivenesssupporting

confidence: 89%

Familial Thrombophilia Associated With Homozygosity for the Cystathionine β-Synthase 833T→C Mutation

Gaustadnes

Rüdiger

Rasmussen

et al. 2000

ATVB

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“…A total of nine variations were detected, and four of them, T257M, R336C, G347S, and T353M, had been previously reported Gaustadnes et al 2002;Dawson et al 1997;Kraus 1994). Five variations, R18C, L154Q, A155V, A288T, and del234D, were novel (Table 2).…”

Section: Mutation Analysismentioning

confidence: 65%

“…In addition, all the patients and their families showed c.1080C/T polymorphism, and c.699C/T polymorphism was found in patient 4 and her family. The c.1080C/T and c.699C/T are known as benign polymorphisms in CpG islands (Kraus 1994).…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Yoo

et al. 2005

J Hum Genet

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Homocystinuria is an autosomal recessive inborn error of metabolism that is most often caused by mutation in the cystathionine beta-synthase (CBS) gene. Patients may develop serious clinical manifestations such as lens dislocation, mental retardation, osteoporosis, and atherothrombotic vascular disease. Over 100 mutations have been reported, but so far, none have been reported in Korea. Mutation analysis of the CBS gene in six Korean patients with homocystinuria was performed by direct sequencing. Eight mutations were identified, including four known mutations (T257M, R336C, T353M, and G347S) and four novel mutations (L154Q, A155V, del234D, and A288T). All patients were compound heterozygotes. To characterize these mutations, normal or mutated forms of CBS were cloned into pcDNA3.1 expression vector followed by transfection into mammalian cells for transient expression. Whereas the expression levels of mutant proteins were comparable to that of normal control, enzyme activities of all the mutant forms were significantly decreased. In addition, a novel single nucleotide polymorphism, R18C, was identified, which showed onethird to two-thirds the enzyme activity of wild type and 1% of the allele frequency in normal control. The spectrum of mutations observed in Korean patients bears less resemblance to those observed in Western countries.

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“…Human CBS also forms multimers, coordinates heme with a bound iron, and contains a regulatory domain that binds the metabolite AdoMet as a possible regulatory mechanism (Shan and Kruger 1998;Meier et al 2001;Christopher et al 2002;Scott et al 2004;Chen et al 2006;Sen and Banerjee 2007). These features suggest control points for enzyme regulation and function, or targets for nutritional and pharmaceutical therapies, that CBS alleles may affect differently.Directed sequencing efforts of patients afflicted with homocystinuria have produced a large catalog of alleles (Kraus et al 2012), with both common and rare alleles (Mudd et al 1985;Kraus 1994;Gallagher et al 1995Gallagher et al , 1998. However, clinical association does not guarantee causality.…”

mentioning

confidence: 99%

“…Directed sequencing efforts of patients afflicted with homocystinuria have produced a large catalog of alleles (Kraus et al 2012), with both common and rare alleles (Mudd et al 1985;Kraus 1994;Gallagher et al 1995Gallagher et al , 1998. However, clinical association does not guarantee causality.…”

mentioning

confidence: 99%

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

et al. 2012

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Cystathionine-b-synthase (CBS) deficiency is a human genetic disease causing homocystinuria, thrombosis, mental retardation, and a suite of other devastating manifestations. Early detection coupled with dietary modification greatly reduces pathology, but the response to treatment differs with the allele of CBS. A better understanding of the relationship between allelic variants and protein function will improve both diagnosis and treatment. To this end, we tested the function of 84 CBS alleles previously sequenced from patients with homocystinuria by ortholog replacement in Saccharomyces cerevisiae. Within this clinically associated set, 15% of variant alleles were indistinguishable from the predominant CBS allele in function, suggesting enzymatic activity was retained. An additional 37% of the alleles were partially functional or could be rescued by cofactor supplementation in the growth medium. This large class included alleles rescued by elevated levels of the cofactor vitamin B6, but also alleles rescued by elevated heme, a second CBS cofactor. Measurement of the metabolite levels in CBS-substituted yeast grown with different B6 levels using LC-MS revealed changes in metabolism that propagated beyond the substrate and product of CBS. Production of the critical antioxidant glutathione through the CBS pathway was greatly decreased when CBS function was restricted through genetic, cofactor, or substrate restriction, a metabolic consequence with implications for treatment.T HE first complete human genome sequence seeded the defining challenge of human genetics for the foreseeable future: interpreting the impact of variations in the sequences of individual human genomes. Comparative genome sequencing reveals an average of one single-nucleotide change per 1200 bp between any two individuals. In the absence of strong Mendelian inheritance and linkage, confirming that any human genotype actually caused a phenotype is a significant challenge given the approximately 3 million genetic variants per person. Indeed, 4000 traits of medical interest show evidence for inheritance but lack a clear determinant (Online Mendelian Inheritance in Man 2012). Next-generation sequencing within small pedigrees (Ng et al. 2010a,b;Fan et al. 2011), or a more narrowly defined clinical phenotype (Schubert et al. 1997), can sometimes disentangle the underlying contribution of a gene to disease. In this work we have taken an approach that complements both increased sequencing capacity and expanded phenotypic description. We used surrogate genetics to assay directly the function of allelic variants and then evaluate their potential contribution to phenotypes of clinical importance.Homocystinuria, elevated levels of the sulfur-containing metabolite homocystine in the urine, illustrates several Reference numbers for publicly available data; GenBank: L14577.1 (CBS); dbSNP: rs17849313 (A69P), rs2229413 (P70L), rs11700812 (R369P); SGD: YGR155W (CYS4) and YDR232W (HEM1 challenges inherent to elucidating the molecular bases of human geneti...

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Molecular basis of phenotype expression in homocystinuria

Cited by 103 publications

References 14 publications

Familial Thrombophilia Associated With Homozygosity for the Cystathionine β-Synthase 833T→C Mutation

Familial Thrombophilia Associated With Homozygosity for the Cystathionine β-Synthase 833T→C Mutation

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

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

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