Identification of lipid binding and lipoprotein lipase activation domains of human apoAV

Sun, Guotao; Bi, Nan; Li, Guoping; Zhu, Xuewei; Zeng, Weiwei; Wu, Gang; Xue, Hong; Chen, Baosheng

doi:10.1016/j.chemphyslip.2006.04.004

Cited by 32 publications

(20 citation statements)

References 33 publications

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“…Soon after the recognition of the first cases, there were indications which suggest the existence of less frequent genetic variants which, in combination with the common allelic variants of the gene, can define haplotypes that are associated with substantial triglyceride level increase. Residues 192-238 are necessary for lipid binding and activation of LPL, while the C-terminal end is not a requisite for APOA5 to bind a folded secondary structure [16]. These rare mutations may cause inheritable hypertriglyceridemia, but they presented at a low frequency and could not be captured by standard genotyping array screenings.…”

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confidence: 99%

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Duga¹,

Sümegi²,

Kisfali³

et al. 2012

Current Medicinal Chemistry

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Apoliporotein A5 (APOA5), a member of the apolipoprotein family, plays a key regulatory role in triglyceride (TG) metabolism. Even though the exact biochemical background of its mechanism is not yet fully understood, diseases associated with this particular gene highlighted its key role in the metabolism of triglycerides in humans. Naturally occurring functional variants of the gene and their natural major haplotypes are known to associate with moderately elevated triglyceride levels, and are also known to confer risk or protection for major polygenic diseases, like coronary heart disease, stroke, or metabolic syndrome. On the other hand, case reports and even robust resequencing studies verified APOA5 mutations as underlying genetic defects behind extreme hypertriglyceridemic phenotype. Soon after the recognition of the first cases, there were indications which suggest the existence of less frequent genetic variants which, in combination with the common allelic variants of the gene, can define haplotypes that are associated with substantial triglyceride level increase. In addition, it became evident, that there are rare mutations of the APOA5 gene which can be associated with specific complex phenotypes and different types of hyperlipoproteinemia, which includes extremely high triglyceride levels with multiple organ pathology. These rare mutations may cause inheritable hypertriglyceridemia, but they presented at a low frequency and could not be captured by standard genotyping array screenings. The identification of new mutations still relies on the direct sequencing of APOA5 gene of patients with hypertriglyceridemia with an unusual pattern, individually or in huge resequencing studies.

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confidence: 99%

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Duga¹,

Sümegi²,

Kisfali³

et al. 2012

Current Medicinal Chemistry

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“…In vitro studies showed that an apoA-V deletion mutant of amino acids 301 to 343 exhibited significantly reduced lipid binding activity. 13 Case 3 was detected peripartum at the time of Caesarean section, and although not confirmed, she also likely has had several recurrent episodes of pancreatitis. Apart from pregnancy, there were no secondary causes of hypertriglyceridaemia present.…”

Section: Discussionmentioning

confidence: 94%

Clinical features and genetic analysis of three patients with severe hypertriglyceridaemia

et al. 2014

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Hypertriglyceridaemia is a common biochemical abnormality that can be due to primary causes or, more commonly, secondary causes. Moderate hypertriglyceridaemia is a risk factor for cardiovascular disease and can develop into severe hypertriglyceridaemia which is a risk factor for acute pancreatitis. Familial chylomicronaemia is a rare autosomal recessive disorder, usually diagnosed in childhood and is characterized by marked hypertriglyceridaemia and biochemical deficiency of lipoprotein lipase (LPL), apolipoprotein (apo) C-II, homozygous (or compound heterozygous) gene mutations in LPL or more rarely, APOC2. Recently, loss-of-function mutations in the APOA5 gene have been reported in patients with severe hypertriglyceridaemia in whom LPL or APOC2 mutations were not found. We describe the clinical features and genetic analysis of three patients with severe hypertriglyceridaemia including novel mutations LPL c.464T>C (p.Leu155Pro) and APOA5 c.823C>T (p.Gln275*).

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“…After the removal of the endoplasmic reticulum signal peptide of 23 amino acids, this mutation would cause truncation at residue 74 of the mature protein (343 amino acids) [54], creating a predicted 10 kDa peptide instead of the 39 kDa complete protein. This peptide, if synthesized (see discussion on NMD below), would lack the essential domain for lipid binding and LPL activation (residues 192 to 238) and therefore is expected to be non-functional [41,55] (Additional file 1: Figure S4 shows our own prediction model of the Apo A-V protein structure). In these previous reports on homozygous patients carrying the Q97X mutation, neither wild-type nor truncated Apo A-V were detected in plasma, thus suggesting a complete Apo A-V deficiency [52,53].…”

Section: Discussionmentioning

confidence: 99%

APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

et al. 2012

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BackgroundSevere hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family.MethodsWe carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives.ResultsA large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls.ConclusionThe Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

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Identification of lipid binding and lipoprotein lipase activation domains of human apoAV

Cited by 32 publications

References 33 publications

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Clinical features and genetic analysis of three patients with severe hypertriglyceridaemia

APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

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