Characterization of two novel pathogenic variants at compound heterozygous status in lipase maturation factor 1 gene causing severe hypertriglyceridemia

Péterfy, Miklós; Bedoya, Candy; Giacobbe, Carola; Pagano, Cristina; Gentile, Marco; Rubba, P.; Fortunato, Giuliana; Taranto, Maria Donata Di

doi:10.1016/j.jacl.2018.07.008

Cited by 10 publications

(4 citation statements)

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“…The first two homozygous LMF1 truncating mutations have previously been experimentally demonstrated to impact LMF1 activity. To date, p.Ser137Leu was identified and reported as the first missense mutation affecting LMF1 function ( Péterfy et al, 2018 ). This variant severely diminishes the expression of mutant LMF1 and dramatically reduces the specific activity of LMF1.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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 in vitro. Whole-exome sequencing (WES) was performed revealing that the severe hypertriglyceridemic proband carried a missense mutation (c.590G > A) in exon 5 of the LPL gene, as well as a missense mutation (c.1523C > T) in exon 10 of the LMF1 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 LMF1 c.1523C > T mutation and the LPL 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 LMF1 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 LMF1 and LPL gene mutations both caused a decreased LPL mass. Moreover, the combination of LMF1 and LPL gene mutations significantly decreased LPL levels compared to their individual effects on the LPL concentration. Both the clinical and in vitro data suggest that severe hypertriglyceridemia was of digenic origin caused by LMF1 and LPL mutation double heterozygosity in this patient.

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Section: Discussionmentioning

confidence: 99%

“…Only three homozygous nonsense LMF1 mutations (p.Tyr439*, p.Tyr460*, and p.Trp464*) have been identified as being causative of hyperchylomicronemia. The p.Ser137Leu missense variant in the LMF1 gene was shown to be causative of severe hypertriglyceridemia through functional analysis ( Péterfy et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…LMF1 is localized to the endoplasmic reticulum and is required for proper synthesis and secretion of LPL and HL. In addition to nonsense mutations that were originally reported, several other mutations, including missense loss-of-function mutations, have been identified in LMF1 [24][25][26][27][28][29] .…”

Section: Advance Publication Journal Of Atherosclerosis and Thrombosismentioning

confidence: 99%

Current Diagnosis and Management of Primary Chylomicronemia

Okazaki

Gotoda

Ogura

et al. 2021

JAT

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tissues 1) . CMs are usually quickly cleared from plasma after an overnight fast. The hallmark of chylomicronemia is persistent elevation of CMs in the fasting state ( 12h). Plasma triglyceride (TG) levels Definition of Chylomicronemia Chylomicrons (CMs) are intestine-derived lipoproteins that transport dietary fat to peripheralCopyright©2021 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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“…These defects may be caused by variants in no less than five different genes, predominantly (about 95%) inherited ones in both alleles of the lipoprotein lipase gene, which, aliased as LPL ( 2 ), is responsible for encoding of the enzyme lipoprotein lipase (LPL; OMIM #238600). Previous studies have shown that the defects directly related to LPL gene variants are also relevant to the majority of severe hyperlipidemia cases ( 3 – 6 ). The rest 5% are the results of variants in other genes involving in LPL functioning, including APOC2 (encoding apolipoprotein CII, activator of LPL; OMIM #207750) ( 7 , 8 ), APOA5 (encoding apolipoprotein AV, activator of LPL; OMIM #144650) ( 9 , 10 ), LMF1 (encoding lipase maturation factor 1, a tissue factor triggering the secretion of functional LPL and hepatic lipase; OMIM #611761) ( 11 , 12 ), and GPIHBP1 (encoding glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1, the molecular platform by which LPL is able to interact with TG-rich lipoproteins, apolipoprotein CII, and apolipoprotein AV on the endothelial surface of capillaries; OMIM #612757) ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

et al. 2022

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BackgroundSevere hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.MethodsThe 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.ResultsThe infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.ConclusionsOur study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

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Characterization of two novel pathogenic variants at compound heterozygous status in lipase maturation factor 1 gene causing severe hypertriglyceridemia

Cited by 10 publications

References 20 publications

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

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

Current Diagnosis and Management of Primary Chylomicronemia

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

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