Genotype-phenotype studies of six novel LPL mutations in Chinese patients with hypertriglyceridemia.
We screened 160 unrelated Chinese hypertriglyceridemic subjects for sequence alterations in the promoter and the 10 exons of the lipoprotein lipase (LPL) gene. We identified one reported mutation (L252R), one common polymorphism (S447X), and six novel mutations: V181I, C283Y, S298R and S338F (found in single individuals), L252V (in two individuals), and A71T (in three individuals). Screening of family members of the above probands revealed a total of 19 mutation carriers, most of whom, though not all, displayed reduced LPL activity and mass when compared to normolipidemic control subjects. In in vitro expression studies, A71T, V181I, L252R, L252V and C283Y decreased the specific activity of the gene product. Interestingly, S298R had no effect on the catalytic activity while S338F increased it. A71T and C283Y reduced the secretion of the mutant proteins significantly while V181I, S298R and S338F had mild effects only. The total LPL mass of all the mutant constructs was reduced compared to that of the wild type construct, probably due to the instabilities of the mutant mRNA or the mutant protein. The heterogeneity in phenotypic effects of these mutations is a likely consequence of their variable effects on proteoglycan binding, conformation and interactions with other secondary genetic or environmental factors.
Chan
Lisa Y S
LY
Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China.
Lam
Ching-Wan
CW
Mak
Ying-Tat
YT
Tomlinson
Brian
B
Tsang
Man-Woo
MW
Baum
Larry
L
Masarei
John R L
JR
Pang
Chi-Pui
CP
D002384:Catalysis; D002681:China; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010641:Phenotype
D008055:Lipids; D004247:DNA; D008071:Lipoprotein Lipase