Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure–function relationships and studies in a compound heterozygous proband
| Autor: | Timothy J. Lyons, Santica M. Marcovina, John J. Albers, P. Haydn Pritchard, Jonny St. Armand, Brett Wagenhorst, Richard L. Klein, Alicia J. Jenkins, George Argyropoulos, W. Timothy Garvey |
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| Rok vydání: | 1998 |
| Předmět: |
Proband
medicine.medical_specialty Apolipoprotein B polymerase chain reaction Sterol O-acyltransferase QD415-436 medicine.disease_cause Compound heterozygosity Biochemistry Endocrinology Internal medicine medicine lipoprotein [a] Fish-Eye Disease Genetics Lecithin cholesterol acyltransferase deficiency Mutation biology substrate recognition binding site familial LCAT deficiency Lecithin Acyltransferase Deficiency Cell Biology medicine.disease high density lipoprotein biology.protein lipids (amino acids peptides and proteins) LCAT activity |
| Zdroj: | Journal of Lipid Research, Vol 39, Iss 9, Pp 1870-1876 (1998) |
| ISSN: | 0022-2275 1870-1876 |
| DOI: | 10.1016/s0022-2275(20)32175-1 |
| Popis: | Two novel mutations were identified in a com- pound heterozygous male with lecithin:cholesterol acyl- transferase (LCAT) deficiency. Exon sequence determina- tion of the LCAT gene of the proband revealed two novel heterozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino acid substitu- tions (Thr13Met and Pro307Ser, respectively). To assess the distinct functional impact of the separate mutant alleles, studies were conducted in the proband's 3-generation pedi- gree. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband's mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. The proband's father and two daughters were heterozygous for the Thr13Met mutation and also displayed low HDL, reduced LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely im- paired in the compound heterozygous proband and was re- duced by 50% in individuals heterozygous for either muta- tion, compared to wild type family members. It is also shown that the two mutations impair both catalytic activity and expression of the circulating protein.— Argyropoulos, G., A. Jenkins, R. L. Klein, T. Lyons, B. Wagenhorst, J. St. Ar- mand, S. M. Marcovina, J. J. Albers, P. H. Pritchard, and W. T. Garvey. Transmission of two novel mutations in a pedi- gree with familial lecithin:cholesterol acyltransferase defi- ciency: structure-function relationships and studies in a compound heterozygous proband. J. Lipid Res. 1998. 39: 1870-1876. |
| Databáze: | OpenAIRE |
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