A Heterozygous LMF1 Gene Mutation (c.1523C>T), Combined With an LPL Gene Mutation (c.590G>A), Aggravates the Clinical Symptoms in Hypertriglyceridemia.

Hypertriglyceridemia is an important contributor to atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Familial hypertriglyceridemia is often caused by mutations in genes involved in triglyceride metabolism. Here, we investigated the disease-causing gene mutations in a Chinese family with hypertriglyceridemia and assessed the functional significance . Whole-exome sequencing (WES) was performed revealing that the severe hypertriglyceridemic proband carried a missense mutation (c.590G > A) in exon 5 of the gene, as well as a missense mutation (c.1523C > T) in exon 10 of the gene. Conservation analysis by Polyphen-2 showed that the 508 locus in the LMF1 protein and 197 locus in the LPL protein were highly conserved between different species. I-TASSER analysis indicated that the c.1523C > T mutation and the c.590G > A mutation changed the tertiary structure of the protein. A decrease in mRNA and protein expression was observed in 293T cells transfected with plasmids carrying the c.1523C > T mutation. Subcellular localization showed that both wild-type (WT) and mutant LMF1 protein were localized at the cell cytoplasm. In the cell medium and cell lysates, these and gene mutations both caused a decreased LPL mass. Moreover, the combination of and gene mutations significantly decreased LPL levels compared to their individual effects on the LPL concentration. Both the clinical and data suggest that severe hypertriglyceridemia was of digenic origin caused by and mutation double heterozygosity in this patient.