This Article Full Text Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koivisto, U.-M. Articles by Kontula, K. Search for Related Content PubMed PubMed Citation Articles by Koivisto, U.-M. Articles by Kontula, K.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1392-1399.)
© 1997 American Heart Association, Inc.

Articles

Familial Moderate Hypercholesterolemia Caused by Asp235Glu Mutation of the LDL Receptor Gene and Co-occurrence of a De Novo Deletion of the LDL Receptor Gene in the Same Family

Ulla-Maija Koivisto; Helena Gylling; Tatu A. Miettinen; ; Kimmo Kontula

From the Departments of Medicine (U.-M.K., H.G., T.A.M., K.K.) and of Pharmacology and Toxicology (U.-M.K.), University of Oulu, and Department of Medicine (K.K.), University of Helsinki (Finland).

Correspondence to Kimmo Kontula, MD, Associate Professor of Medicine, Department of Medicine, University of Helsinki, FIN 00290, Helsinki, Finland.

Abstract We identified a large family in which a hitherto unreported point mutation of the LDL receptor gene (Asp235Glu) cosegregated with moderately elevated serum LDL cholesterol concentration. Within one generation, the mean serum total and LDL cholesterol levels in four heterozygous carriers of this mutation (7.76±1.46 and 5.89±1.56 mmol/L, respectively) were significantly (P<.05) higher than the corresponding concentrations in their five nonaffected siblings (5.81±0.57 and 3.77±0.54 mmol/L, respectively). Lipid levels in carriers of the Asp235Glu mutation were, however, markedly lower than the corresponding total and LDL cholesterol levels (about 12 and 10 mmol/L, respectively) in heterozygous patients with the two common LDL receptor mutations (FH-Helsinki and FH-North Karelia). None of the four siblings in the age range of 54 to 69 years had experienced a myocardial infarction, although symptoms suggestive of coronary artery disease were present in two and tendon xanthomas were found in one. Expression of the mutant receptor in COS cells indicated an approximately 50% to 70% reduction of LDL-binding activity compared with the normal receptor. One patient (female, aged 39 years) had severe hypercholesterolemia in the range of 13 to 20 mmol/L when untreated, extensive coronary artery disease as demonstrated by angiography, and extensor tendon xanthomatosis. In addition to the Asp235Glu mutation, she was found to have a de novo deletion of exons 14 and 15 in her other LDL receptor allele. In this subject, the total LDL receptor activity of mitogen-stimulated blood lymphocytes was very low. In conclusion, along with another LDL receptor gene mutation (FH-Espoo or deletion of exon 15) described by us previously, the Asp235Glu mutation (designated as FH-Keuruu) indicates that moderate varieties of inherited hypercholesterolemia may result from LDL receptor gene mutations of mild expression.

Key Words: LDL receptor gene mutation • familial hypercholesterolemia

This article has been cited by other articles:

				A. F. Vuorio, H. Turtola, and K. Kontula Neonatal Diagnosis of Familial Hypercholesterolemia in Newborns Born to a Parent With a Molecularly Defined Heterozygous Familial Hypercholesterolemia Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 3332 - 3337. [Abstract] [Full Text]