Phenotypic expression in double heterozygotes for familial hypercholesterolemia and familial defective apolipoprotein B-100
| Autor: | B. Hermelin, Isabelle Ginon, Jean Luc De Gennes, Elizabeth Villain, Lagarde Jp, Chantal Bernard, Gilbert Bereziat, Marie Christine Federspiel, Pascale Benlian, François Dairou, Véronique Bertrand |
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| Rok vydání: | 1996 |
| Předmět: |
Adult
Male medicine.medical_specialty Heterozygote Apolipoprotein B Genotype Molecular Sequence Data Locus (genetics) Familial hypercholesterolemia Biology Hyperlipoproteinemia Type II Internal medicine Genetics medicine Missense mutation Humans Allele Child Genetics (clinical) Apolipoproteins B Base Sequence Heterozygote advantage Middle Aged medicine.disease Phenotype Pedigree Endocrinology LDL receptor Apolipoprotein B-100 biology.protein lipids (amino acids peptides and proteins) Female |
| Zdroj: | Human mutation. 7(4) |
| ISSN: | 1059-7794 |
| Popis: | Variability in the expression of monogenic lipid disorders may be observed in patients carrying the same DNA mutation, suggesting possible genetic or environmental interactions. Our objective was to investigate the genotype-phenotype relationships in two unrelated French patients with an aggravated expression of a dominantly inherited hypercholesterolemia. In probands, segregation analysis complemented by DNA sequencing identified heterozygous defective alleles and mutations on two nonallelic loci for two monogenic lipid disorders: familial hypercholesterolemia at the low density lipoprotein (LDL) receptor locus and familial defective apolipoprotein B-100 at the locus encoding its ligand, apolipoprotein B-100. The LDL-receptor missense mutations had been reported in French Canadians. The apolipoprotein B mutation was the Arg3500Gln founder mutation in Northern Europe. Probands had an unusual phenotype of aggravated hypercholesterolemia that was complicated with premature coronary arterial disease, although remaining responsive to lipid-lowering drugs. This phenotype was distinct from that observed in their heterozygous relatives and distinct from those observed in FH or FDB homozygotes. These cases refer to a new class of patients with digenic lipid disorders, defined by specific clinical features that result from the combined effects of two independent loci. Moreover, the observed phenotype of aggravated hypercholesterolemia gives further evidence that receptor and ligand play distinct roles in regulating LDL metabolism. Although uncommon, these cases give insight into the molecular mechanisms that underly the clinical variability of inherited hypercholesterolemia. |
| Databáze: | OpenAIRE |
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