Prevalence of alleles encoding defective lipoprotein lipase in hypertriglyceridemic patients of French Canadian descent

Minnich, Anne; Kessling, Anna M.; Roy, Madeleine; Giry, Claude; DeLangavant, Ghislaine; Lavigne, Jacques; Lussier‐Cacan, Suzanne; Davignon, Jean

doi:10.1016/s0022-2275(20)39760-1

Cited by 47 publications

(3 citation statements)

References 29 publications

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“…Due to founder effects, some populations have higher carrier frequencies of LOF LPL variants than others. For example, the carrier frequency of defective LPL alleles is as high as 1 in 40 in some regions of the French Canadian population, which has the highest prevalence of homozygous LPL deficiency around the world ( 24 , 25 ). Unfortunately, such carrier frequency data was not available for the Chinese population.…”

Section: Discussionmentioning

confidence: 99%

Novel pathogenic variant combination in LPL causing familial chylomicronemia syndrome in an Asian family and experimental validation in vitro: a case report

H¹,

Wang²

2022

Transl Pediatr

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Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder, typically caused by biallelic pathogenic variants in the LPL gene. Lipoprotein lipase, encoded by the LPL gene, catalyzes the hydrolysis of triglycerides, and its deficiency or dysfunction can lead to chylomicronemia and potentially fatal recurrent acute pancreatitis.Case Description: Here, we report an Asian family with FCS due to compound heterozygous LPL variants. The 4-year-old patient presented with splenomegaly and severe hypertriglyceridemia, specifically chylomicronemia which resulted in abnormal coagulation measured by a turbidity-based assay. Based on the clinical symptoms and family history, the diagnosis of FCS was suspected, and confirmed by the identification of compound heterozygous variants in the LPL gene (c.461A>G; p.His154Arg and c.788T>A; p.Leu263Gln) in the patient, inheriting one from each parent. According to the clinical and genetic findings, the patient was diagnosed with FCS. In vitro experimental validation found that the LPL p.H154R pathogenic variant reduced the expression of lipoprotein lipase and decreased its lipolytic activity, while the LPL p.L263Q pathogenic variant mainly impaired its lipolytic activity.Conclusions: FCS was molecularly diagnosed using whole exome sequencing in the case presented.Caution should be taken when interpretating the coagulation profile of FCS patients due to increased plasma turbidity caused by the high chylomicron levels. When interpreting abnormal coagulation profiles measured by turbidity-based assay, the possibility of lipemic blood (or chylomicronemia) should be considered and the presence of this phenomenon might indicate the diagnosis of FCS. In vitro experiments showed that the two LPL variants impaired lipoprotein lipase expression and function.

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Section: Discussionmentioning

confidence: 99%

Novel pathogenic variant combination in LPL causing familial chylomicronemia syndrome in an Asian family and experimental validation in vitro: a case report

H¹,

Wang²

2022

Transl Pediatr

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“…The frequency is approximately the same as that of heterozygote carriers of an LDL receptor gene mutation, but can be much higher in inbred populations (34). The expression of HTG and low HDL cholesterol in heterozygotes with one defective LPL allele has been studied in numerous families (6)(7)(9)(10)(11)(12). The results of these studies reveal that many of these heterozygotes have normal plasma triglyceride concentrations, whereas in others plasma triglycerides are moderately elevated.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with two defective LPL alleles exhibit all the clinical features of the disease (2,3), whereas in heterozygous carriers of one defective allele, fasting triglyceride levels can be both normal or moderately increased (4)(5)(6)(7)(8)(9). The phenotypic expression of heterozygous LPL deficiency has been the subject of numerous studies (6,7,9,10). Age, obesity, pregnancy, insulin resistance, and lipid-raising drugs were reported to play a role (6).…”

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confidence: 99%

Two novel mutations in the lipoprotein lipase gene in a family with marked hypertriglyceridemia in heterozygous carriers: potential interaction with the polymorphic marker D1S104 on chromosome 1q21–q23

Hölzl

Kraft

Wiebusch

et al. 2000

Journal of Lipid Research

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Two novel mutations in the lipoprotein lipase (LPL) gene are described in an Austrian family: a splice site mutation in intron 1 (3 bp deletion of nucleotides ؊ 2 to ؊ 4) which results in skipping of exon 2, and a missense mutation in exon 5 which causes an asparagine for histidine substitution in codon 183 and complete loss of enzyme activity. A 5year-old boy who exhibited all the clinical features of primary hyperchylomicronemia was a compound heterozygote for these two mutations. Nine other family members were investigated: seven were heterozygotes for the splice site mutation, one was a heterozygote for the missense mutation, and one had two wild-type alleles of the LPL gene. LPL activity in the post-heparin plasma of the heterozygotes was reduced to 49-79% of the mean observed in normal individuals. Two of the heterozygotes had extremely high plasma triglyceride levels; in three of the other heterozygotes the plasma triglycerides were also elevated. As plasma triglycerides in carriers of one defective LPL allele can be normal or elevated, the heterozygotes of this family have been studied for a possible additional cause of the expression of hypertriglyceridemia in these subjects. Body mass index, insulin resistance, mutations in other candidate genes (Asn291Ser and Asp9Asn in the LPL gene, apoE isoforms, polymorphisms in the apoA-II gene and in the apoAI-CIII-AIV gene cluster, and in the IRS-1 gene) could be ruled out as possible factors contributing to the expression of hypertriglyceridemia in this family. A linkage analysis using the allelic marker D1S104 on chromosome 1q21-q23 suggested that a gene in this region could play a role in the expression of hypertriglyceridemia in the heterozygous carriers of this family, but the evidence was not sufficiently strong to prove this assumption. Nevertheless, this polymorphic marker seems to be a good candidate for further studies. -Hölzl, B.

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Family study of lipoprotein lipase gene polymorphisms and plasma triglyceride levels

et al. 1996

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To better characterize the role of the lipoprotein lipase (LPL) gene in the determination of triglyceride levels in healthy subjects, a study was performed in 193 nuclear families (384 parents, means age = 42.0 ± 5.2 years; 399 offspring, mean age = 14.6 ± 4.3 years) volunteering to have a free health checkup examination. The pattern of familial resemblance was compatible with a zero correlation between spouses, a weak father‐offspring correlation (0.099 ± 0.054; P < 0.07), and significant mother‐offspring (0.235 ± 0.053; P < 10−4) and sib‐sib (0.294 ± 0.064; P < 10−4) correlations. Associations of triglyceride levels with the LPL HindIII and PvuII polymorphisms were investigated by a familial measured genotype analysis, specifying sex‐ and age‐dependent polymorphism effects. The effects associated with both polymorphisms were significant only in fathers, the H+ and P+ alleles being associated with raised triglyceride levels. The HindIII and PvuII polymorphisms explained 3.5% and 3%, respectively, of the variability of triglycerides in fathers. The relationship was weakened after prior adjustment on body mass index, but remained significant for PvuII. Because of the lack of effect in mothers and offspring, the polymorphisms did not contribute to the covariance of triglyceride levels in relatives. In conclusion, this family study showed a weak relationship of the HindIII and PvuII polymorphisms to plasma triglyceride levels in young healthy male subjects. The effects detectable only in fathers suggest a possible modulation of the LPL expression by hormonal or lifestyle factors. © 1996 Wiley‐Liss, Inc.

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Prevalence of alleles encoding defective lipoprotein lipase in hypertriglyceridemic patients of French Canadian descent

Cited by 47 publications

References 29 publications

Novel pathogenic variant combination in LPL causing familial chylomicronemia syndrome in an Asian family and experimental validation in vitro: a case report

Novel pathogenic variant combination in LPL causing familial chylomicronemia syndrome in an Asian family and experimental validation in vitro: a case report

Two novel mutations in the lipoprotein lipase gene in a family with marked hypertriglyceridemia in heterozygous carriers: potential interaction with the polymorphic marker D1S104 on chromosome 1q21–q23

Family study of lipoprotein lipase gene polymorphisms and plasma triglyceride levels

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