Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia

Abstract

Objective The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG >10 mmol/L) it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam. Methods The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored HDL-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls. Results 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. Conclusion 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 our understanding of the molecular basis of this phenotype associated with acute pancreatitis, and may help to guide future individualized therapeutic strategies.

A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis

“…21 Three missense variants in MCF2L (NM_001112732.1), ZC3HC1 (NM_016478.3) and CAMSAP1 (NM_015447.3) were identified and confirmed with Sanger sequencing as previously described using the following primer pairs: MCF2L forward 5′-TGC TTT TGC TTT GAT GGA TG-3′ and reverse 5′-CAT TCC AGC CCC CTG AAG-3′; ZC3HC1 forward: 5′-GAG AAA ACT CTC TTT TTC ATT CC-3′ and reverse 5′-CAC CCA AAT AAG CTA AGT GAA TAC-3′; CAMSAP1 5′-AAA CAG ATG CTA CCA ATC CCT TAC-3′ and reverse 5′-CCT CTT CCA AAG ATG CCA AC-3′. 22 The data are registered in the LOVD database under screening number 00027156 (http://databases.lovd.nl/ shared/screenings/0000027156).…”

Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia

“…While LPL and APOC2 gene mutations have been known for decades to be a cause of familial hyperchylomicronemia ( 4-6 ), mutations in the APOA5 or glycosylphosphatidylinositol-anchored HDL-binding protein 1 ( GPIHBP1 ) genes have been found more recently to explain some cases of this disease in which no LPL or APOC2 mutations were found ( 7-9 ). APOA5 variants have also been linked to the polygenic hyperlipidemia types IIb, III, IV, and V as well as to cardiovascular disease risk ( 3,(10)(11)(12)(13)(14).ApoA-V was fi rst identifi ed and characterized as a liver preprotein of 366 amino acid residues that is secreted 08-1147 (to F.B.-V.), 11-01076 (to F.B.-V.), 10-00277 (to J.J.), and SAF2010-15668 (to P.F.-P.) …”

Novel Combined GPIHBP1 Mutations in a Patient with Hypertriglyceridemia Associated with CAD

“…Hence, the absence of GPIHBP1 is accompanied by severe hypertriglyceridemia 6) . In humans, the prevalence of GPIHBP1 mutations has been reported to be 5% among patients with severe hypertriglyceridemia 27) .…”