Familial lipoprotein lipase (LPL) deficiency: a catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy
| Autor: | France Mailly, Jutta Palmen, David P.R. Muller, Tracy Gibbs, June Lloyd, John Brunzell, Paul Durrington, Kostas Mitropoulos, John Betteridge, Gerald Watts, Hans Lithell, Franco Angelico, Steve E. Humphries, Philippa J. Talmud |
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| Rok vydání: | 1997 |
| Předmět: |
Adult
Sweden Genotype Genetic Carrier Screening DNA Mutational Analysis Infant Newborn Infant Middle Aged United Kingdom Genetic Heterogeneity Lipoprotein Lipase Phenotype Genes Italy Child Preschool COS Cells Mutation Genetics Animals Humans Hyperlipoproteinemia Type I Child Genetics (clinical) Polymorphism Single-Stranded Conformational Triglycerides |
| Zdroj: | Human mutation. 10(6) |
| ISSN: | 1059-7794 |
| Popis: | The aim of this study was to identify mutations in the lipoprotein lipase (LPL) gene in 20 unrelated patients with familial lipoprotein deficiency (FLLD) and to investigate the genotype/phenotype relationship. The previously reported G188E mutation (Monsalve et al., J Clin Invest 86:728-734, 1990) was screened for and found to be present in seven individuals (12/40 alleles). In addition, three patients were heterozygous for the 2.0 kb insertion (Langlois et al., Proc Nalt Acad Sci US 86:948-952, 1989). Two approaches were taken for new mutation detection; single-strand conformation polymorphism and sequencing to identify micro-mutations in the proximal promoter and exons 1-9 of the LPL gene and Southern blotting to identify gross mutations. Ten different point mutations were found (W86G, A158T, H183Q, G188E, S193R, P207L, L252X, N291S, M301T, L303P). Additionally, a two nucleotide deletion in exon 6 (delta1006-1007), a six nucleotide deletion in exon 8 (delta1441-1447), and a silent substitution in the wobble position of codon E118 were identified. In vitro mutagenesis and expression in COS-B cells suggested that the A158T and S193R substitutions virtually abolished enzyme activity. In analysing the genotype/phenotype relationship, there was no strong association between age at diagnosis, severity of symptoms, lipid levels, and the nature/position of the mutation. Triglyceride levels, however, were higher in compound heterozygotes compared to true homozygotes, possibly reflecting increased instability of heterodimers. Overall, 29 of 40 (72.5%) mutant alleles were identified. Failure to identify the mutation in 11 alleles might reflect the inadequacy of the method or the possibility that mutations lie within regions of the gene not screened in the study because of lack of availability of sequence. |
| Databáze: | OpenAIRE |
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