Bedoya Candy, Thomas Rishi, Bjarvin Anna, Ji Wilbur, Samara Hanien, Tai Jody, Green Laurie, Frost Philip H, Malloy Mary J, Pullinger Clive R, Kane John P, Péterfy Miklós
Department of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, USA (Dr Bedoya, Thomas, Bjarvin, Ji, Samara, Tai, and Péterfy).
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA (Drs Green, Malloy, Pullinger, and Kane).
J Clin Lipidol. 2025 Jan-Feb;19(1):95-104. doi: 10.1016/j.jacl.2024.10.004. Epub 2024 Oct 19.
The genetic basis of hypertriglyceridemia (HTG) is complex and includes variants in lipase maturation factor 1 (LMF1), an endoplasmic reticulum (ER)-chaperone involved in the post-translational activation of lipoprotein lipase (LPL).
The objective of this study was to identify and functionally characterize biallelic LMF1 variants in patients with HTG.
Genomic DNA sequencing was used to identify biallelic LMF1 variants in HTG patients without deleterious variants in LPL, apolipoprotein C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) or apolipoprotein A-V (APOA5). LMF1 variants were functionally evaluated by in silico analyses and assessing their impact on LPL activity, LMF1 protein expression, and specific activity in transiently transfected HEK293 cells.
We identified four homozygous LMF1 variants in patients with severe HTG: two novel rare variants (p.Asn147Lys and p.Pro246Arg) and two low-frequency variants (p.Arg354Trp and p.Arg364Gln) previously reported at heterozygosity. We demonstrate that all four variants reduce the secretion of enzymatically active LPL by impairing the specific activity of LMF1, whereas p.Asn147Lys also diminishes LMF1 protein expression.
This study extends the role of LMF1 as a genetic determinant in severe HTG and demonstrates that rare and low-frequency LMF1 variants can underlie this condition through distinct molecular mechanisms. The clinical phenotype of patients affected by partial loss of LMF1 function is consistent with multifactorial chylomicronemia syndrome (MCS) and suggests that secondary factors and additional genetic determinants contribute to HTG in these subjects.
高甘油三酯血症（HTG）的遗传基础复杂，包括脂肪酶成熟因子1（LMF1）的变异，LMF1是一种内质网（ER）伴侣蛋白，参与脂蛋白脂肪酶（LPL）的翻译后激活。
本研究旨在鉴定HTG患者中的双等位基因LMF1变异并对其进行功能表征。
采用基因组DNA测序来鉴定HTG患者中的双等位基因LMF1变异，这些患者在LPL、载脂蛋白C-II（APOC2）、糖基磷脂酰肌醇锚定高密度脂蛋白结合蛋白1（GPIHBP1）或载脂蛋白A-V（APOA5）中无有害变异。通过计算机分析并评估其对LPL活性、LMF1蛋白表达以及瞬时转染的HEK293细胞中比活性的影响，对LMF1变异进行功能评估。
我们在重度HTG患者中鉴定出四个纯合的LMF1变异：两个新的罕见变异（p.Asn147Lys和p.Pro246Arg）以及两个先前报道为杂合状态的低频变异（p.Arg354Trp和p.Arg364Gln）。我们证明，所有这四个变异均通过损害LMF1的比活性来降低具有酶活性的LPL的分泌，而p.Asn147Lys还会减少LMF1蛋白的表达。
本研究扩展了LMF1作为重度HTG遗传决定因素的作用，并证明罕见和低频的LMF1变异可通过不同的分子机制导致这种疾病。受LMF1功能部分丧失影响的患者的临床表型与多因素乳糜微粒血症综合征（MCS）一致，表明次要因素和其他遗传决定因素导致了这些受试者的HTG。
