Cystathionine β‐Synthase (CBS) Deficiency: Genetics

Abstract

Cystathionine β‐synthase is an enzyme that catalyzes the condensation of homocysteine and serine to cystathionine. Its deficiency, an autosomal recessive trait resembling Marfan syndrome, is caused by more than 120 different mutations that affect ribonucleic acid processing or properties of the enzyme. The most common pathogenic mutation, c.833T > C, arose by a complex evolutionary process as evidenced by its relatedness to the alleles that contain the frequent polymorphism 844ins68.

A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

“…Therefore, our assay may be unsuitable for detecting some pathogenic variants in this regulatory domain (e.g., p.Asp444Asn). Further complicating variant interpretation, a number of variants in the regulatory domain have previously been observed to render CBS biochemically hyperactive and yet paradoxically cause symptoms typical for CBS deficiency [15,[24][25][26]63]. Nevertheless, most truncating variants falling within the regulatory domain did behave like null variants suggesting that our assay can still capture some large-effect variants in this domain.…”

“…The disease was discovered in 1962 [19] and soon after was shown to be caused by a deficiency of CBS activity in the liver [20]. Since the identification of the first disease-causing CBS variants [21], several hundred alleles have been identified in homozygous or compound-heterozygous homocystinuria patients [22], many of which have been further genetically and biochemically characterized [23][24][25][26][27][28], yielding~200 annotated pathogenic variants [3,29]. About 13% of the variants deposited in the CBS Mutation Database [22] are genomic deletions, frameshift mutations, premature termination codons, or missplicing variants, some of which affect CBS mRNA stability via nonsense-mediated decay (NMD) [30], while others affect protein folding or biochemical function.…”

“…However, the majority of these variants (about 87%) are missense variants. Missense variants may affect catalytic function with only minor conformational changes or, substantially more frequently, lead to misfolding amenable to in vitro correction by chemical chaperones or the presence of cofactors [23][24][25][26][31][32][33][34]. Regardless of the underlying molecular mechanism, most pathogenic variants yield substantially decreased or null activity of CBS.…”

Diversity of cystathionine β-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion

“…However, early treatment by administration of high doses of pyridoxine and/or by methionine restriction combined with betaine administration has proven effective in preventing many complications of this disease [ Mudd et al, 2001 ]. The clinical, biochemical, and molecular aspects of CBS deficiency have recently been reviewed in detail [ Kožich and Kraus, 2001 ; Mudd et al, 2001 ].…”

“…Despite the detrimental impact of the mutation on enzymatic properties, homozygosity or compound heterozygosity for the c.833C allele is consistently associated with a mild clinical phenotype, both in humans and in transgenic mice [ Mudd et al, 2001 ; Wang et al, 2005 ]. More importantly, carriership of at least one c.833C allele in CBS-deficient patients confers clinical and biochemical responsiveness to vitamin B 6 administration, and consequently necessitates a less severe therapeutic regimen [ Kožich and Kraus, 2001 ; Mudd et al, 2001 ].…”