Abstract
The LMF1 (lipase maturation factor 1) gene encodes a protein involved in lipoprotein lipase and hepatic lipase maturation. Homozygous mutations in LMF1 leading to severe hypertriglyceridemia (SHTG) are rare in the literature. A few additional rare LMF1 variants have been described with poor functional studies. The aim of this study was to assess the frequency of LMF1 variants in a cohort of 385 patients with SHTG, without homozygous or compound heterozygous deleterious mutations identified in lipoprotein lipase (LPL), apolipoprotein A5 (APOA5), apolipoprotein C2 (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) genes, and to determine their functionality. LMF1 coding variants were screened using denaturing high-performance liquid chromatography followed by direct sequencing. In silico studies of LMF1 variants were performed, followed by invitro functional studies using human embryonic kidney 293T (HEK-293T) cells cotransfected with vectors encoding human LPL and LMF1 cDNA. LPL activity was measured in cell culture medium after heparin addition using human VLDL-TG as substrate. Nineteen nonsynonymous coding LMF1 variants were identified in 65 patients; 10 variants were newly described in SHTG. Invitro, p.Gly172Arg, p.Arg354Trp, p.Arg364Gln, and p.Arg537Trp LMF1 variants decreased LPL activity, and the p.Trp464Ter variant completely abolished LPL activity. We identified a young girl heterozygote for the p.Trp464Ter variant and a homozygote carrier of the p.Gly172Arg variant with a near 50% decreased LPL activity invitro and invivo. The study confirms the rarity of LMF1 variants in a large cohort of patients with SHTG. LMF1 variants are likely to be involved in multifactorial hyperchylomicronemia. Partial LMF1 defects could be associated with intermittent phenotype as described for p.Gly172Arg homozygous and p.Trp464Ter heterozygous carriers.
Highlights
Severe hypertriglyceridemia (HTG), defined by plasma triglycerides (TG) > 10 mmol/L, is more likely to have genetic causes than moderate HTG
LMF1 gene encodes for a transmembrane protein located in the endoplasmic reticulum, critical for lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) maturation, by acting as a lipase chaperone (3)
3 nonsense homozygous mutations of LMF1 gene leading to hyperchylomicronemia have been identified (4-6)
Summary
Severe hypertriglyceridemia (HTG), defined by plasma triglycerides (TG) > 10 mmol/L, is more likely to have genetic causes than moderate HTG. Monogenic familial hyperchylomicronemia syndrome (FCS), a rare autosomal recessive disease, is due to homozygous or compound heterozygous loss of function mutations in genes that regulate TG rich-lipoprotein lipolysis such as lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) genes. Hyperchylomicronemic patients exhibit multigenic sporadic severe HTG (multifactorial chylomicronemia, MCM) with a large interplay of life style factors or comorbidities such as metabolic syndrome, obesity, type 2 diabetes and a combination of common small-effect variants and/or rare heterozygous large effect variants in genes involved in the regulation TG metabolism, with incomplete penetrance (1,2). 3 nonsense homozygous mutations of LMF1 gene leading to hyperchylomicronemia have been identified (4-6). A few other rare variants have been published in moderate to severe HTG with no clear evidence for their functionality (7-9)
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