Genetic and phenotypic heterogeneity in familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Six newly identified defective alleles further contribute to the structural heterogeneity in this disease.
Open Access
- 1 February 1993
- journal article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 91 (2) , 677-683
- https://doi.org/10.1172/jci116248
Abstract
The presence of lecithin:cholesterol acyltransferase (LCAT) deficiency in six probands from five families originating from four different countries was confirmed by the absence or near absence of LCAT activity. Also, other invariate symptoms of LCAT deficiency, a significant increase of unesterified cholesterol in plasma lipoproteins and the reduction of plasma HDL-cholesterol to levels below one-tenth of normal, were present in all probands. In the probands from two families, no mass was detectable, while in others reduced amounts of LCAT mass indicated the presence of a functionally inactive protein. Sequence analysis identified homozygous missense or nonsense mutations in four probands. Two probands from one family both were found to be compound heterozygotes for a missense mutation and for a single base insertion causing a reading frame-shift. Subsequent family analyses were carried out using mutagenic primers for carrier identification. LCAT activity and LCAT mass in 23 genotypic heterozygotes were approximately half normal and clearly distinct from those of 20 unaffected family members. In the homozygous patients no obvious relationship between residual LCAT activity and the clinical phenotype was seen. The observation that the molecular defects in LCAT deficiency are dispersed in different regions of the enzyme suggests the existence of several functionally important structural domains in this enzyme.Keywords
This publication has 25 references indexed in Scilit:
- Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin-cholesterol acyltransferase (Thr347----Met).Journal of Clinical Investigation, 1992
- An amino acid exchange in exon I of the human lecithin:cholesterol acyltransferase (LCAT) gene is associated with Fish Eye DiseaseBiochemical and Biophysical Research Communications, 1992
- Molecular defect in familial lecithin:Cholesterol acyltransferase (LCAT) deficiency: A single nucleotide insertion in LCAT gene causes a complete deficient type of the diseaseBiochemical and Biophysical Research Communications, 1991
- Differential phenotypic expression by three mutant alleles in familial lecithin:cholesterol acyltransferase deficiencyThe Lancet, 1991
- Lecithin-cholesterol acyltransferase (LCAT) deficiency with a missense mutation in exon 6 of the LCAT geneBiochemical and Biophysical Research Communications, 1991
- Molecular Basis of Different Forms of Metachromatic LeukodystrophyNew England Journal of Medicine, 1991
- A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities.Journal of Clinical Investigation, 1991
- Simplified Turbidimetric Determination of Apolipoproteins A-I, A-II and B Using a Microtitre Methodcclm, 1988
- Lecithin‐cholesterol‐acyltransferase deficiency: autosomal recessive transmission in a large kindred*Clinical Genetics, 1981
- Radioimmunoassay of human plasma lecithin-cholesterol acyltransferase.Journal of Clinical Investigation, 1981