FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the low density lipoprotein receptor gene in a German patient with homozygous familial hypercholesterolemia

We describe the characterization of a novel mutation in the low density lip oprotein receptor (LDL-R) gene in a patient with true homozygous familial h ypercholesterolemia (FH). The combined use of denaturing gradient gel elect rophoresis (DGGE) and sequencing of genomic DNA revealed a guanine to adeni ne base substitution at nucleotide position 1013 of the LDL-R cDNA. This po int mutation results in a change from cysteine to tyrosine at amino acid re sidue 317 of repeat A of the epidermal growth factor (EGF) precursor homolo gy domain. Binding, uptake and degradation of iodinated LDL in skin fibrobl asts from the homozygous patient were less than 10% of normal. In contrast, binding, uptake and degradation of iodinated VLDL was reduced by only 60, 30, and 38%, respectively. Incubation of the patient's fibroblasts in the p resence of cholesterol diminished the residual binding of VLDL by 50%, sugg esting that the loss of the highly conserved cysteine at position 317 resul ts in a LDL-R that fails to bind LDL, but retains some ability to bind VLDL by interacting with the apolipoprotein E. Both parents were heterozygous f or the C317Y mutation. Interestingly, however, the father presented with ma rkedly elevated levels of triglycerides and VLDL cholesterol, whereas his L DL cholesterol was unexpectedly low. The mother of the index patient had on ly slightly elevated LDL cholesterol. These observations testify to the bio logical complexity of genotype-environment interactions in individuals carr ying mutations at the LDL-R locus and indicate that genetic analysis import antly complements the clinical and biochemical diagnosis of patients with h yperlipidemia. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.