Homozygous familial hypercholesterolemia: a paradigm for phenotypic variation

Most, if not all, inborn errors of metabolism manifest phenotypic heterogeneity in their clinical presentation. The term "penetrance" has been used to describe the degree to which a given genotype expresses itself in the phenotype of the individual. Although many explanations for this phenomenon have been put forward, the molecular bases for this have been difficult to define. The investigation of the disease familial hypercholesterolemia (FH) has been used as a paradigm at many different levels. This condition, in which a wide variety of mutations in the low density lipoprotein (LDL) receptor gene leads to elevated concentrations of LDL particles has a wide array of clinical manifestations that are variably expressed in both patients who are heterozygous and homozygous for mutations at the LDL receptor allele. Progress in understanding lipoprotein metabolism, atherogenesis, and the development of molecular biology and transgenic expression techniques converge to utilize homozygous FH as a paradigm for understanding the molecular basis of penetrance. Elucidation of the key factors in altering the clinical features expressed by patients with FH have theoretical implications in understanding the polygenic nature of atherosclerosis as well as practical ramifications in the treatment of patients with FH.