Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families

Familial hypercholesterolemia (FH) is a common inherited disorder of metabolism characterized clinically by high levels of low-density lipoprotein (LDL) in plasma owing to reduced catabolism. This leads to accelerated atherosclerosis and thus to an increased risk of coronary heart disease. FH is usually caused by defects in the gene for either the LDL receptor or apolipoprotein B (apoB), the ligand for the LDL receptor. Elsewhere, we have described two unrelated patients with phenotypic homozygous FH. Both patients were offspring of consanguineous unions, and linkage to either the gene for the LDL receptor or the gene for apoB was excluded in both. Their cells in culture do not degrade LDL, despite the presence of normal surface binding of LDL to the LDL receptor. This observation suggests that the patients may be homozygous for a defective gene that encodes a component of the internalization pathway. We first excluded linkage of the defect to known genes for proteins reported to be involved in internalization of receptors in clathrin-coated pits. We then performed genomewide homozygosity mapping. Genotyping of 500 polymorphic markers in three affected and seven unaffected members of the first pedigree showed that recessive hypercholesterolemia in this family is localized to a single chromosomal region on 1p36-p35. Genotyping of two affected and five unaffected members of the second pedigree provided further evidence of linkage to this locus, thereby mapping the disease-causing gene to a 12-cM region on chromosome 1p36-p35, with a combined LOD score of 5.3 in these unrelated families. Identification of the gene in this region may lead to new insights into the mechanisms of LDL receptor-mediated uptake of LDL by cells and may help to identify further genetic risk factors for premature atherosclerosis.