A specific type of gene mutation affecting the LDL receptor has been found in many Finnish patients with familial hypercholesterolemia (FH). The mutant allele is characterized by a 9.5-kb deletion extending from intron 15 to exon 18. Molecular cloning and sequencing of a cDNA segment corresponding to the deleted allele indicated that the mutant receptor differs radically from the normal one because of loss of the domains encoded by exons 16, 17, and 18. The carboxy-terminal portion of the normal receptor, comprising the amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. The mutant allele was found to occur in 23 (50%) of 46 unrelated FH patients with an established functional defect in the LDL receptor. In cultured fibroblasts from the FH patients with the 9.5-kb deletion, both receptor-mediated binding and internalization of 125I-LDL were lower than normal, the former, on average, by 25%, and the latter, on average, by 50%. This combined functional defect probably results from both impaired attachment and impaired internalization of the mutated receptor. It remains to be investigated whether this Finnish type of LDL receptor gene mutation, here designated FH-Helsinki, occurs in other ethnic groups.