Charlotte L. Scholtz

Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction

OBJECTIVE This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction (IUGR). STUDY DESIGN DNA was extracted from blood samples of 54 patients with placental vasculopathy (18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and amplified by the polymerase chain reaction (PCR). The resulting fragments were subjected to restriction enzyme analysis and resolved by gel electrophoresis. RESULTS A significant association could be demonstrated between mutation A1298C and both abruptio placentae and IUGR. Combined heterozygosity for mutations C677T and A1298C was detected in 22.2% of abruptio placentae cases. CONCLUSIONS Combined heterozygosity for MTHFR mutations C677T and A1298C may represent a genetic marker for abruptio placentae.

Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation‐based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B‐100 (FDB) and seven low‐density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder‐type ‘South African mutations’ were responsible for FH in ∼20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B‐100 mutation R3500Q. The detection of multiple founder‐type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

A double mutant LDL receptor allele in a Cypriot family with heterozygous familial hypercholesterolemia

Abstract Two novel mutations Q363X and D365E were identified in the low-density lipoprotein receptor gene in a Cypriot patient with heterozygous familial hypercholesterolemia. Restriction enzyme analysis of the index case and seven of her family members, by using AvaII and PvuII respectively, demonstrated that the two exon 8 mutations are transmitted in cis within the family. The disease phenotype is probably caused by the stop-363 mutation; this would result in a truncated protein that would probably be rapidly degraded in the extracellular space.

Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element

DNA samples of 2303 individuals from nine different population groups were screened for variant -175g-->t in the promoter region of the low-density lipoprotein receptor (LDLR) gene. The -175g-->t variant detected at carrier frequencies of 3-10% in different African population groups was absent in the Caucasian and Asian (Chinese) individuals studied. In contrast to previous findings in Black South Africans where this polymorphism predominated in patients with familial hypercholesterolaemia (FH), it occurred at a significantly lower frequency in hypercholesterolaemics from the recently admixed Coloured population of South Africa compared with population-matched controls (P<0.0001). Haplotype and mutation analysis excluded the likelihood that this finding is due to association with a specific disease-related mutation in FH patients, although reversal of the positive association with FH observed in the Black population may, at least in part, be due to admixture linkage disequilibrium. Transient transfection studies in HepG2 cells demonstrated that the -175t allele is associated with a non-significant decrease ( approximately 7%) of LDLR transcription in the absence of sterols. The data presented in this study raise the possibility that the -175g-->t polymorphism may have subtle effects that become clinically important within certain genetic and/or environmental contexts.