High Prevalence of the I278T Mutation of the Human Cystathionine β-Synthase Detected by a Novel Screening Application

Abstract

SummaryClassical homocystinuria due to cystathionine beta-synthase deficiency is one of the disorders revealing a high risk of thromboembolic events and vascular disease. This autosomal-recessively inherited metabolic disorder is considered to be rare with an estimated prevalence of 1:130,000 in the German population. In this study, we developed a novel multiplex PCR generating allele specific fragment lengths to analyse individual genotypes of the two most frequent cystathionine beta-synthase alterations, the I278T mutation, which is worldwide found on up to the half of homocystinuric alleles, and the adjacent polymorphism 844ins68. Screening of 200 unrelated German control subjects revealed a frequency of heterozygosity of 1.5% for I278T corresponding to a calculated frequency of homozygosity of 1:17.800. Our data indicate that homocystinuria due to cystathionine β-synthase deficiency is a frequently unrecognized disorder resulting in a high risk of thromboembolic events.

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma

“…Allele frequencies of the control group did not significantly differ from those reported in the literature (Harmon et al, 1999;Linnebank et al, 2000Linnebank et al, , 2001; Table 1). The MS c.2756A4G polymorphism (G-allele) was significantly less frequent in patients than in controls.…”

“…Five functional polymorphisms were analysed as previously described: Cystathionin beta-synthase (CBS) c.833T4C (I278 T) and 844ins68 (splice variant), methionine synthase (MS) c.2756A4G (D919G), and methylenetetrahydrofolate reductase (MTHFR) c.677C4T (A222 V) and c.1298A4C (E429A). With the exception of CBS I278 T, these polymorphisms have a high prevalence within the healthy German population with allele frequencies ranging between 0.08 and 0.34 (Harmon et al, 1999;Linnebank et al, 2000Linnebank et al, , 2001.…”

Cystathionine?-synthase deficiency in Georgia (USA): Correlation of clinical and biochemical phenotype with genotype

“…I278T is a common alteration in homocystinurics from Northern Europe and Australia, and has been observed in some patients from United States Kraus et al, 1999]. Two population-based studies from Denmark and Germany suggest that 1.5% of the population is heterozygous for this mutation, suggesting that the frequency of individuals homozygous for this alteration may be as high as 1 in 20,000, while in the Czech and Slovak republics it was estimated to be 1 in 83,000 Linnebank et al, 2001;Sokolova et al, 2001]. All of the patients in our cohort containing I278T were Caucasian and presumably of FIGURE 1.…”

A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency

“…In the Czech and Slovak Republics, among 1284 newborns screened 5 heterozygotes were identified, a frequency of 0.389 %, giving a predicted frequency of homozygosity of 1:264,000 [8]. Among unrelated healthy adults, heterozygote frequencies of 1.5% were found in Germany (200 screened; predicted homozygote frequency, 1:17,800) [9]; and 0.4% in The Netherlands (500 screened; predicted homozygote frequency, 1:250,000) [10]. …”