A novel LDLR mutation, H190Y, in a Utah kindred with familial Hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causi ng twice normal low-density lipoprotein (LDL) cholesterol levels early in c hildhood and very early coronary disease in both men and women. Treatment w ith multiple medications together with diet can normalize cholesterol level s in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly un der-diagnosed new cases of FH among members of known families with FH and o ver-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the ear ly diagnosis of heterozygous FH. In the course of investigations of coronar y artery disease in Utah, we identified a family whose proband showed eleva ted plasma levels of LDL cholesterol. To carry out molecular genetic diagno sis of the disease, we screened DNA samples for mutations in all 18 exons a nd the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleoti de position 631, causing substitution of tyrosine for histidine at codon 19 0 in exon 4 of the LDLR gene. The mutant allele-specific amplification meth od was used to examine 12 members of the family recruited for the diagnosis . This method helped to unequivocally diagnose 7 individuals as heterozygou s for this particular LDLR mutation, while excluding the remaining 5 indivi duals from carrier status with FH.