New rare genetic variants of LMF1 gene identified in severe hypertriglyceridemia

Dancer, Marine; Filippo, Mathilde Di; Marmontel, Oriane; Valéro, René; Rivarola, Maria Del Carmen Piombo; Peretti, Noël; Caussy, Cyrielle; Krempf, Michel; Vergès, Bruno; Mahl, Murielle; Marçais, Christophe; Moulin, Philippe; Charrière, Sybil

doi:10.1016/j.jacl.2018.06.018

Cited by 24 publications

(10 citation statements)

References 21 publications

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“…This variable clinical expression may be, at least partly, explained by the existence of an established secondary etiological factor, alcohol abuse, in the proband but not in the diseased mother and older sister. Although interplay between primary and secondary etiological factors in causing HTG-AP has been described in the literature [17,18], to our best knowledge, the present study is the first to demonstrate the possible effect of alcohol abuse in modifying the Fig. 4 Functional characterization of the LPL p.Gln118* variant.…”

Section: Discussionmentioning

confidence: 67%

“…However, in most cases, the cause of HTG is complex [15]. Severe HTG was recently shown to be primarily polygenic [16], and there is increasing appreciation of the interplay between primary and secondary etiological factors in causing severe HTG [17,18]. In this study, we reported a novel LPL nonsense variant in one typical Chinese family with HTG-AP history and discussed insights into the complex etiology of HTG-AP gleaned from the so far reported pathogenic LPL nonsense variants.…”

Section: Introductionmentioning

confidence: 85%

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Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis

Chen

et al. 2020

Lipids Health Dis

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Background: Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG. Objectives: The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister). Methods: The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship. Results: We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes. Conclusions: Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 85%

Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis

Chen

et al. 2020

Lipids Health Dis

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“…Specifically, they co-transfected HEK293T cells with the wild-type LPL expression vector and the LMF1 mutant expression vector of interest; and then measured the LPL activity in the culture media of the co-transfected HEK-293 T cells. As such, Serveaux Dancer and colleagues found that both the LMF1 p.Tyr439* and p.Trp464* nonsense variants caused an almost complete loss of the LPL activity [13]. The LMF1 c.1024C > T (p.Arg342*) variant reported here, which removes ~ 100 more residues from the C terminus of the protein as compared to p.Tyr439* and p.Trp464*, can be reasonably concluded to cause a complete functional loss of the affected LMF1 allele.…”

Section: Discussionmentioning

confidence: 99%

“…A particularly interesting finding of the Serveaux Dancer study is that in one of their subjects with severe HTG, their mutational analysis of the LPL , APOC2 , APOA5 , GBIHBP1 and LMF1 genes identified only a single and heterozygous deleterious variant, LMF1 p.Trp464* (N.B. one of the aforementioned loss-of-function LMF1 nonsense mutations) [13]. Prior to their report, all heterozygous carriers of nonsense LMF1 variants had been described to have either normal or at most borderline HTG.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel and heterozygous LMF1 nonsense mutation in an acute pancreatitis patient with severe hypertriglyceridemia, severe obesity and heavy smoking

Chen

Yang

et al. 2019

Lipids Health Dis

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BackgroundHypertriglyceridemia (HTG) is one of the most common etiologies of acute pancreatitis (AP). Variants in five genes involved in the regulation of plasma lipid metabolism, namely LPL, APOA5, APOC2, GPIHBP1 and LMF1, have been frequently reported to cause or predispose to HTG.MethodsA Han Chinese patient with HTG-induced AP was assessed for genetic variants by Sanger sequencing of the entire coding and flanking sequences of the above five genes.ResultsThe patient was a 32-year-old man with severe obesity (Body Mass Index = 35) and heavy smoking (ten cigarettes per day for more than ten years). At the onset of AP, his serum triglyceride concentration was elevated to 1450.52 mg/dL. We sequenced the entire coding and flanking sequences of the LPL, APOC2, APOA5, GBIHBP1 and LMF1 genes in the patient. We found no putative deleterious variants, with the exception of a novel and heterozygous nonsense variant, c.1024C > T (p.Arg342*; rs776584760), in exon 7 of the LMF1 gene.ConclusionsThis is the first time that a heterozygous LMF1 nonsense variant was found in a HTG-AP patient with severe obesity and heavy smoking, highlighting an important interplay between genetic and lifestyle factors in the etiology of HTG.Electronic supplementary materialThe online version of this article (10.1186/s12944-019-1012-9) contains supplementary material, which is available to authorized users.

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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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New rare genetic variants of LMF1 gene identified in severe hypertriglyceridemia

Cited by 24 publications

References 21 publications

Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis

Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis

Identification of a novel and heterozygous LMF1 nonsense mutation in an acute pancreatitis patient with severe hypertriglyceridemia, severe obesity and heavy smoking

Current Diagnosis and Management of Primary Chylomicronemia

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