FAMILIAL LIPOPROTEIN-LIPASE (LPL) DEFICIENCY - A CATALOG OF LPL GENE-MUTATIONS IDENTIFIED IN 20 PATIENTS FROM THE UK, SWEDEN, AND ITALY

The aim of this study was to identify mutations in the lipoprotein lip ase (LPL) gene in 20 unrelated patients with familial lipoprotein defi ciency (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 i ndividuals (12/40 alleles). In addition, three patients were heterozyg ous for the 2.0 kb insertion (Langlois et al., Proc Nalt Acad Sci US 8 6:948-952, 1989). Two approaches were taken for new mutation detection ; single-strand conformation polymorphism and sequencing to identify m icro-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 (Delta 1006-1007), a six nucleotide deletion in exon 8 (Delta 1411- 1447), and a silent substitution in the wobble position of codon E118 were identified. In vitro mutagenesis and expression in COS-B cells su ggested that the A158T and S193R substitutions virtually abolished enz yme activity. In analysing the genotype/phenotype relationship, there was no strong association between age at diagnosis, severity of sympto ms, lipid levels, and the nature/position of the mutation. Triglycerid e levels, however, were higher in compound heterozygotes compared to t rue homozygotes, possibly reflecting increased instability of heterodi mers. Overall, 29 of 40 (72.5%) mutant alleles were identified. Failur e 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. (C) 1997 Wiley-Liss, Inc.