Genetic and functional studies of the LMF1 gene in Thai patients with severe hypertriglyceridemia

Plengpanich, Wanee; Muanpetch, Suwanna; Charoen, Supannika; Kiateprungvej, Arunrat; Khovidhunkit, Weerapan

doi:10.1016/j.ymgmr.2020.100576

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…The compound heterozygosity in family B explains that the presence of homozygous p.G36D variant in LMF1 along with heterozygous changes in LPL and GPIHBP1 causes the severe elevation in the affected father BB1. The p.G36D of LMF1 was earlier reported in a Thai family with F-HTG with one patient being homozygous and 4 were heterozygous ( Plengpanich et al, 2020 ).…”

Section: Discussionmentioning

confidence: 53%

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman

et al. 2022

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Familial hypertriglyceridemia (F-HTG) is an autosomal disorder that causes severe elevation of serum triglyceride levels. It is caused by genetic alterations in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. The mutation spectrum of F-HTG in Arabic populations is limited. Here, we report the genetic spectrum of six families of F-HTG of Arab ancestry in Oman. Methods: six Omani families affected with triglyceride levels >11.2 mmol/L were included in this study. Ampli-Seq sequencing of the selected gene panels was performed. Whole-exome sequencing and copy number variant analysis were also performed in cases with negative exome results. Three novel pathogenic missense variants in the LPL gene were identified, p.M328T, p.H229L, and p.S286G, along with a novel splice variant c.1322+15T > G. The LPL p.H229L variant existed in double heterozygous mutation with the APOA5 gene p.V153M variant. One family had a homozygous mutation in the LMF1 gene (c.G107A; p.G36D) and a heterozygous mutation in the LPL gene (c.G106A; p.D36N). All affected subjects did not have a serum deficiency of LPL protein. Genetic analysis in one family did not show any pathogenic variants even after whole-exome sequencing. These novel LPL and APOA5 mutations are not reported in other ethnic groups. This suggests that patients with F-HTG in Oman have a founder effect and are genetically unique. This warrants further analysis of patients of F-HTG in the Middle East for preventative and counseling purposes to limit the spread of the disease in a population of high consanguinity.

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Section: Discussionmentioning

confidence: 53%

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman

et al. 2022

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“…Since her LPL levels were not measured, there is a possibility that she carried a different mutation, which could also increase the LPL activity. It was reported that the p.Thr143Met mutation, which could increase the activity of LPL, was identified in a patient with Familial hyperchylomicronemia ( Plengpanich et al, 2020 ).…”

Section: Discussionmentioning

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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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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Assessment of Zinc-alfa2 Glycoprotein (ZAG) and Lipase Maturation Factor 1 (LMF1) concentration in children with chronic kidney disease

Roszkowska-Bjanid¹,

Świętochowska²,

Bjanid³

et al. 2021

Physiol Res

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ZAG (zinc-α2-glycoprotein) - adipokine, may participate in the mechanism of malnutrition in chronic kidney disease (CKD) as cachexia factor. The transmembrane protein of the endoplasmic reticulum - lipase maturation factor 1 (LMF1) is necessary for the secretion and enzymatic activity of lipases and lowering triglycerides level. The aim of the study was to evaluate these markers - ZAG and LMF1, their potential importance in CKD in children. The study included 59 children and adolescents aged 10.7±5.0 years with CKD. Compared with healthy children, serum and urine ZAG levels were higher in children with CKD. A similar relationship was obtained in the comparison of girls and boys between the above groups. We showed a reduced serum and urine concentration of LMF1 in children with CKD. Additionally, ZAG and LMF1 levels in children below 10 years of age and above 10 were no different. There was also no correlation between these markers and serum creatinine (except negative correlation of urinary ZAG), albumin, cholesterol, triglycerides. LMF1 concentration correlated positively with vitamin D level in dialyzed patients. To conclude, elevated serum ZAG levels in children with CKD document that selective kidney damage results in the rise of ZAG concentration, however the specific role of this marker in malnutrition was not documented. Reduced serum LMF1 concentration in children with CKD, did not correlate with standard parameters used to assess lipid metabolism and severity of CKD. The usefulness of LMF1 as the marker of the lipid metabolism disturbances in children with CKD was not proven.

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Genetic and functional studies of the LMF1 gene in Thai patients with severe hypertriglyceridemia

Cited by 3 publications

References 21 publications

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman

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

Assessment of Zinc-alfa2 Glycoprotein (ZAG) and Lipase Maturation Factor 1 (LMF1) concentration in children with chronic kidney disease

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