Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10 -20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237͞S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237͞S238 deletion had reduced MCP levels and Ϸ50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated Ϸ50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.
To extend our understanding of potential stepwise genetic alterations that may underlie tumor progression from low-grade astrocytomas to glioblastomas, histopathologic and comparative genomic hybridization analyses were performed on tumor specimens from 68 primary lesions, including 40 glioblastomas, 10 anaplastic and 18 low-grade astrocytomas. The number of aberrations per case increased towards the higher grade tumors (grade II: 1.66+/-1.49; grade III: 2.80+/-1.68; grade IV: 3.02+/-1.07; F=6.955, p=0.002). A gain of 7/7q was common and the most frequently seen aberration in low-grade astrocytomas, whereas loss of 10q was the most frequently seen anomaly in anaplastic astrocytomas and glioblastomas. Chromosome 7p amplification was only detected in glioblastomas. Chromosome 10/10q deletion and combination of 1p, 19q and 17p deletions were specific to high-grade astrocytic tumors. Sequences of chromosome 7 and 10 seem to have pivotal roles in the biology of human gliomas. The genomic copy deletions of chromosomes 1p and 19q might provide an alternative mechanism in the genesis of astrocytomas.
Prostate cancer is the most common cause of cancer deaths in men and is a major health problem worldwide. Methylene tetrahydrofolate reductase (MTHFR) plays an important role for folate metabolism and is also an important source for DNA methylation and DNA synthesis (nucleotide synthesis). The objective of this study was to investigate the relationship between the A1298C and C677T polymorphisms of the MTHFR gene and prostate cancer in the Turkish population. In our study, 93 prostate cancer patients between the ages of 50-89 and a control group of 166 benign prostate hyperplasia patients were evaluated. C677T and A1298C polymorphism ratios were compared among these two groups, and an analysis was made to see if there is a statistically meaningful difference. In this study, it has been observed that C677T polymorphism of the MTHFR gene produces no statistically significant difference for T allele frequency and the genotype frequency in prostate cancer patients and male controls with benign prostate hyperplasia not having prostate cancer, whereas it has been observed that A1298C polymorphism produces a statistically significant difference for C allele frequency in prostate cancer patients and controls and that it also produces a statistically marginal significance for genotype frequencies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.