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A double mutant [N543H+2393del9] allele in the LDL receptor gene in familial hypercholesterolemia: effect on plasma cholesterol levels and cardiovascular disease
Author(s) -
Castillo S.,
Reyes G.,
Tejedor D.,
Mozas P.,
Suarez Y.,
Lasuncion M.A.,
Cenarro A.,
Civeira F.,
Alonso R.,
Mata P.,
Pocovi M.
Publication year - 2002
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9087
Subject(s) - familial hypercholesterolemia , missense mutation , biology , allele , compound heterozygosity , exon , ldl receptor , mutant , mutation , heterozygote advantage , cholesterol , genetics , gene , endocrinology , microbiology and biotechnology , medicine , lipoprotein
Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor gene. During a survey of mutations of LDL receptor gene in Spanish FH patients we found two mutations in the same allele: a missense N543H mutation in exon 11 and a 9bp inframe deletion (2393del9) located in exon 17. This double mutant allele was founded in 10 out of 458 unrelated patients: one homozygous FH [N543H+2393del9] + [N543H+2393del9], one compound heterozygote [N543H+2393del9] + [W‐18X+E256K] and 8 heterozygotes. Flow cytometric analysis showed a defective LDL binding (20% of normal value) and internalization (23%) in lymphocytes from the homozygous patient; furthermore, studies of mitogen‐stimulated lymphocytes demonstrated that the ability of LDL to support cell proliferation was impaired. Unexpectedly, not all carriers of the double mutant allele develop hypercholesterolemia and, furthermore, cholesterol‐lowering treatment of the homozygous patient resulted in a 58% LDL cholesterol reduction. In conclusion, the phenotypic expression in the homozygous and heterozygous patients presented here, as well as the LDL‐receptor residual activity, allowed the classification of this mutation as mild extending the group of mild mutations found at homozygosity. © 2002 Wiley‐Liss, Inc.