Genetic studies of the cystathionine beta‐synthase gene and myelomeningocele

Abstract

BACKGROUND Among infants born with spina bifida, the most common defect is myelomeningocele (MM). The prevention of MM by maternal periconceptual folic acid (FA) supplementation has been extensively studied. The protective effect provided by FA suggests that the genes involved in folate metabolism, such as cystathionine beta-synthase (CBS), warrant further investigation. METHODS This study sequenced the DNA from 96 patients with MM to identify novel potential disease causing variants across the 17 exons of the CBS gene. The frequencies of known SNPs were identified and sequences that differed from the reference sequences were considered novel variants. Statistical analysis was performed using 2-sided Fisher's exact test to compare frequencies of SNPs between groups of patients and the known population frequencies. RESULTS We found a new variant in Exon 3 in one patient that result in a G/A change subsequently encoding a stop codon. Additionally, we found a new variant in the 3′-UTR of exon 17. Allele frequencies for ten known SNPs were determined: rs234706, rs72058776, rs1801181, rs6582281, rs71872941, rs12613, rs706208, rs706209, rs73906420, and rs9982921. Of the remaining 48 known SNPs, all tested DNAs were homozygous for the major allele. CONCLUSION We identified a previously undescribed variant in Exon 3 that encodes a stop codon, thus halting downstream translation of the CBS protein. According to the Human Splice Finder, the 3′-UTR variant found in Exon 17 is predicted to abolish the recognition sites for two splice binding factors, SRp40 and SF2/ASF. The functional significance of the 3′-UTR mutation needs to be investigated.

Novel cystathionine β‐synthase gene mutations in a Filipino patient with classic homocystinuria

“…These mutations are the first CBS mutations reported in a Filipino patient. The four known SNP found in this study are benign polymorphisms that have been previously described [13][14][15] and were found not to be associated with the disease. …”

“…13 This suggests that presence of the rs706209 SNP in CBS may affect the CBS pre-mRNA splicing prior to CBS mRNA translation, which may lead to an aberrant CBS protein. The functional significance of this, however, still needs to be investigated.…”

CBS gene polymorphism and promoter methylation‐mediating effects on the efficacy of folate therapy in patients with hyperhomocysteinemia

“…CBS rs2851391 was associated with a change in postmethionine load Hcy levels and plasma Hcy levels of subjects with rs2851391 TT genotype were significantly higher compared to that of the TC and CC genotypes . The presence of CBS rs706209 may affect pre‐mRNA splicing, which could generate an aberrant CBS protein and consequently affect Hcy metabolism …”

“…A genome‐wide association study in European countries demonstrated that rs2851391 was associated with plasma Hcy . The relationship between CBS rs706209 and folate/Hcy metabolism was also investigated . However, there were no studies on the connection about these single nucleotide polymorphisms (SNPs) with the efficacy of folate treatment for HHcy.…”

Relationship of the MTHFD1 (rs2236225), eNOS (rs1799983), CBS (rs2850144) and ACE (rs4343) gene polymorphisms in a population of Iranian pediatric patients with congenital heart defects

“…The CBS gene is localized at 21q22.3 and spans over 30 kb and consists of 23 exons [21]. So far, more than hundreds of mutations in CBS gene had been identified, the major of which are missense mutations and correlated with homocystinuria.…”