No abstract

Homocysteine levels are elevated in mothers of neural tube defect (NTD) children, which may be due to a disturbed folate or vitamin B12 metabolism. Vitamin B12 is transported to the tissues by transcobalamin (TC). We previously showed that a low holo-TC/total-TC ratio is a risk factor for NTD, possibly due to an impaired binding of vitamin B12 to TC. The coding region of the TC gene of 12 individuals was analysed for genetic variations responsible for a disturbed vitamin B12 binding. The influence of the genetic variations observed on total-TC, holo-TC, holo-TC/total-TC, erythrocyte vitamin B12, plasma homocysteine concentrations and risk for NTD was explored in 42 mothers of a child with NTD and in 73 female controls. Direct sequencing analyses revealed five single nucleotide polymorphisms (SNPs). Three SNPs affected total-TC concentrations, whereas two SNPs seem to affect the binding of vitamin B12. None of the genotypes defined by the SNPs had a significant effect on homocysteine levels, or was associated with an increased NTD risk. Among the five SNPs observed only P259R could partly explain the reduced proportion of vitamin B12 bound to TC, which has been associated with an increased risk for having a child with NTD. Some of the variants studied affected total-TC and holo-TC/total-TC ratio but a larger study population is required to elucidate whether these SNPs influence delivery of vitamin B12 to the tissue, influence homocysteine levels and whether they are associated with an increased NTD risk.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine b-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT ± PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.

No abstract

Abstract. In the 1960s, the Arabian oryx was one of the most endangered species in the world, extinct in the wild and surviving in only a few captive herds. The present day population of over 2000 descends from a small number of founders and may have restricted genetic variation for important adaptive genes. We have examined the amount of genetic variation for a class II gene in the major histocompatibility complex thought to be the most important genetic basis for pathogen resistance in vertebrates. We found three very divergent alleles, which on average, differed by 24 nucleotides and 15 amino acids in the 236-bp fragment we examined. Using single-strand conformation polymorphism, we found that in a sample of 57 animals, the alleles were in Hardy-Weinberg proportions, although one allele was found only in four heterozygous individuals. The average heterozygosity for the 22 amino acid positions involved in antigen binding was 0.165, three times as high as that for the 56 amino acids not involved with antigen binding. Because the three alleles have such divergent sequences, it is likely that they may recognize peptides from quite different pathogens. As a result, maintenance of these variants should be considered as a goal in the captive breeding program of the Arabian oryx.

No abstract

Homocysteine, a sulphur amino acid, is a branch-point intermediate of methionine metabolism. It can be degraded in the transsulphuration pathway to cystathionine, or remethylated to methionine via the remethylation pathway. In both pathways, major genetic defects that cause enzyme de ciencies are associated with very high plasma homocysteine concentrations and excretion of homocystine into the urine. Mildly elevated plasma homocysteine concentrations are thought to be an independent and graded risk factor for both arterial occlusive disease and venous thrombosis. Genetic defects in genes encoding enzymes involved in homocysteine metabolism, or depletion of important cofactors or (co)substrates for those enzymes, including folate, vitamin B 12 and vitamin B 6 , may result in elevated plasma homocysteine concentrations. Plasma homocysteine concentrations are also in uenced by dietary and lifestyle factors. In the last decade, several studies have been conducted to elucidate the genetic determinants of hyperhomocysteinaemia in patients with cardiovascular disease. We report on both environmental and genetic determinants of hyperhomocysteinaemia and give a detailed overview of all the genetic determinants that have been reported to date.

In the 1960s, the Arabian oryx was one of the most endangered species in the world, extinct in the wild and surviving in only a few captive herds. The present day population of over 2000 descends from a small number of founders and may have restricted genetic variation for important adaptive genes. We have examined the amount of genetic variation for a class II gene in the major histocompatibility complex thought to be the most important genetic basis for pathogen resistance in vertebrates. We found three very divergent alleles, which on average, differed by 24 nucleotides and 15 amino acids in the 236-bp fragment we examined. Using single-strand conformation polymorphism, we found that in a sample of 57 animals, the alleles were in Hardy-Weinberg proportions, although one allele was found only in four heterozygous individuals. The average heterozygosity for the 22 amino acid positions involved in antigen binding was 0.165, three times as high as that for the 56 amino acids not involved with antigen binding. Because the three alleles have such divergent sequences, it is likely that they may recognize peptides from quite different pathogens. As a result, maintenance of these variants should be considered as a goal in the captive breeding program of the Arabian oryx.