ABSTRACT
OBJECTIVES: To investigate the association of parental hyperhomocysteinemia, C677T Methylene tetrahydrofolate reductase (MTHFR) polymorphism and DNA damage with recurrent pregnancy loss (RPL). DESIGN AND METHODS: A case-control study. Reverse phase HPLC, PCR-RFLP and Cytokinesis blocked micronuclei assay were used to assess total plasma homocysteine, C677T MTHFR polymorphism and DNA damage respectively. Student t-test, ANOVA and Fisher exact test were used for statistical analysis. RESULTS: Maternal [mean: 11.6+/-5.0 versus 8.6+/-4.2 micromol/L, odds ratio (OR): 4.48] and paternal [mean: 19.6+/-9.5 versus 14.2+/-7.4 micromol/L, OR: 6.92] hyperhomocysteinemia, paternal age [OR: 1.16], paternal MTHFR 677T allele [OR: 2.30] and DNA damage were found to increase the risk for RPL. DNA damage showed positive correlation with plasma homocysteine and MTHFR 677T allele. CONCLUSIONS: Parental hyperhomocysteinemia, paternal age, paternal C677T MTHFR polymorphism and DNA damage are risk factors for RPL. DNA damage showed positive correlation with plasma homocysteine and MTHFR 677T allele.
Subject(s)
Embryo Loss/genetics , Genetic Predisposition to Disease , Hyperhomocysteinemia/enzymology , Hyperhomocysteinemia/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Parents , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Amino Acid Substitution/genetics , Case-Control Studies , DNA Damage , Embryo Loss/enzymology , Female , Gene Frequency/genetics , Homocysteine/blood , Humans , Male , Micronuclei, Chromosome-Defective , Pregnancy , Recurrence , Young AdultABSTRACT
Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.
