Mutations in iLPL/i, iAPOC2/i, iAPOA5/i, iGPIHBP1/i and iLMF1/i in patients with severe hypertriglyceridaemia
Journal of Internal Medicine, 08/17/2012
Surendran RP et al. – The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n=3), APOC2 (n=1) and APOA5 (n=2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved the understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies.Methods
- The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI–anchored high–density lipoprotein (HDL)–binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls.
- In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL ( n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8).
- In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%).
- In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function.
- Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype.