Human genetic selection on the MTHFR 677C>T polymorphism.

BACKGROUND: The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA). METHODS: A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman probes. A section of our population (n = 276) born in 1980-1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period. RESULTS: An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980-1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98. CONCLUSION: Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations.

Manifold decrease of sialic acid synthase in fetal Down syndrome brain.

BACKGROUND: Down syndrome (DS, trisomy 21) is the most common genetic cause of mental retardation. A large series of biochemical defects have been observed in fetal and adult DS brain that help in unraveling the molecular mechanisms underlying mental retardation. AIMS: As sialylation of glycoconjugates plays an important role in brain development, this study aimed to look at the sialic acid metabolism by measuring sialic acid synthase (SAS; N-acetylneuraminate synthase) in early second trimester fetal control and DS brain. RESULTS: In this regard, protein profiling was performed by two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption/ionization mass-spectrometry followed by database search and subsequent quantification of spot using specific software. SAS, the enzyme catalyzing synthesis of N-acetyl-neuraminic acid (syn: sialic acid) was represented as a single spot and found to be significantly and manifold reduced (P < 0.01) in cortex of fetuses with DS (control vs. DS, 0.052 +/- 0.025 vs. 0.012 +/- 0.006). CONCLUSION: The intriguing finding of the manifold decrease of SAS in DS fetal cerebral cortex as early as in the second trimester of pregnancy may help to explain the brain deficit observed in DS. Decreased SAS may well lead to altered sialic acid metabolism, required for brain development and, more specifically, for sialylation of key brain proteins, including neuronal cell adhesion molecule and myelin associated glycoprotein.

A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss.

Low maternal folate or vitamin B12 status has been implicated in numerous pregnancy complications including spontaneous abortion. The primary aim of this study was to test a polymorphism within the trifunctional folate enzyme MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthetase) for an association with a mother's risk of having an unexplained second trimester pregnancy loss. We genotyped 125 women who had at least one unexplained spontaneous abortion or intrauterine fetal death between 13 and 26 weeks gestation and 625 control women with no history of prior pregnancy loss. Our study is the first to identify an association between the MTHFD1 1958G-->A (R653Q) polymorphism and the maternal risk of having an unexplained second trimester pregnancy loss. Women who are MTHFD1 1958AA homozygous have a 1.64-fold increased risk of having an unexplained second trimester loss compared to women who are MTHFD1 1958AG or 1958GG [OR 1.64 (1.05-2.57), P = 0.03]. It has been reported that polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), 677C-->T (A222V), transcobalamin II (TCII), 776C-->G (P259R), are associated with pregnancy loss. Both variants were tested in this study. Neither showed evidence of significantly affecting the maternal risk of having a second trimester pregnancy loss. In conclusion, the MTHFD1 1958AA genotype may be an important maternal risk factor to consider during pregnancy.

Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality.

BACKGROUND: SCO2 is a cytochrome c oxidase (COX) assembly gene that encodes a mitochondrial inner membrane protein that probably functions as a copper transporter. Mutations in SCO2 have been associated with severe COX deficiency and early-onset fatal infantile hypertrophic cardiomyopathy, encephalopathy, and neurogenic muscle atrophy. Fetal wastage has not been described in association with mutations of SCO2. OBJECTIVE: To investigate a case of early spontaneous abortion in a family carrying mutations in SCO2. DESIGN: Case report. Patients Spontaneous abortion in the first trimester occurred in a woman whose first pregnancy had also resulted in a miscarriage in the first trimester and whose only child had died at 53 days of life from cardioencephalomyopathy. This child was a compound heterozygote for mutations in SCO2, and her parents were heterozygous for each mutation. MAIN OUTCOME MEASURES: Mutations in the abortus by sequencing the SCO2 gene and confirmation of the point mutations as determined by restriction fragment length polymorphism analysis. RESULTS: As in the previous affected child, we found a missense mutation (E140K) and a nonsense mutation (Q53X) in the abortus. CONCLUSIONS: The typical clinical presentation of SCO2 mutations is severe, rapidly progressive hypertrophic cardiomyopathy that presents in the neonatal period and is often associated with respiratory difficulties, metabolic acidosis, and hypotonia. The experience in this family suggests that mutations in SCO2 may also be associated with early spontaneous abortions and fetal wastage.