Characterization of Mutations in the Cystathionine β-Synthase Gene in Irish Patients with Homocystinuria

Gallagher, Paula; Naughten, E. R.; Hanson, Naomi Q.; Schwichtenberg, Kerry; Bignell, Michelle; Yuan, Min; Ward, Pat; Yap, Sufin; Whitehead, Alexander S.; Tsai, Michael Y.

doi:10.1006/mgme.1998.2771

Cited by 11 publications

(18 citation statements)

References 20 publications

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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.…”

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confidence: 99%

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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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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.…”

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confidence: 99%

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

et al. 2012

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“…The response to betaine was greatest among patients 1 and 2 who had mutations previously described as B6-nonresponsive (NR) 25,24,30 compared to patients who were heterozygous for mutant alleles previously defined as B6-responsive. [31][32][33] The dramatic falls in total plasma homocysteine in all 5 patients were reflected in the mean decrease of over 47.4 mol/L. Although we observed 4/5 patients with a near doubling of their plasma methionine during maximal betaine therapy, the mean plasma methionine in our betaine treatment group did not change.…”

Section: Discussionmentioning

confidence: 86%

“…Two Caucasian patients (patients 4 and 3) were compound heterozygotes for the common European I278T mutation, an L101P alteration observed in several Irish patients, and a novel D376N mutation, respectively. 22,23 One Caucasian patient (Patient 2) was homozygous for a V320A mutation previously observed in a single Norwegian patient. 24 Two American Black patients (patients 5 and 1) possessed a T353M allele.…”

Section: Genotypes Of Patients Studiedmentioning

confidence: 82%

Cystathionine β-synthase deficiency: Effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria

Singh

Kruger

Wang

et al. 2004

Genetics in Medicine

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“…Her clinical picture permits concluding that c.684C>A is associated with severe phenotype and pyridoxine non-responsiveness. Mutations affecting glutamine in position 228 have been reported previously: homozygosity for p.N228S (Kruger et al, 2003), or compound heterozygosity for p.N228K substitution due to either c.684C>G (Gallagher et al, 1998) or c.684C>A (Gaustadnes et al, 2002) transversions. Association of all these mutations with severe phenotype suggests functional importance of glutamine in position 228 in the CBS polypeptide.…”

Section: Other Mutations Found In the Study Groupmentioning

confidence: 84%

Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria

et al. 2004

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Homocystinuria due to cystathionine β-synthase (CBS) deficiency is an inherited disorder of homocysteine transsulfuration, which manifests by neurological, vascular and connective tissue involvement. So far, 130 pathogenic mutations have been recognized in the CBS gene. We examined 10 independent alleles in Polish patients suffering from CBS deficiency, and we detected four already described mutations (c.1224-2A>C, c.684C>A, c.833T>C, and c.442G>A) and two novel mutations (c.429C>G and c.1039+1G>T). The pathogenicity of the novel mutations was demonstrated by expression in E.coli. This is the first published communication on mutations leading to CBS deficiency in Poland.

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Characterization of Mutations in the Cystathionine β-Synthase Gene in Irish Patients with Homocystinuria

Cited by 11 publications

References 20 publications

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

Cystathionine β-synthase deficiency: Effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria

Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria

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