title: Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant.
abstract: Deficiency of apoprotein A-V (apoA-V) can cause hypertriglyceridemia. In an 11 months old boy presenting with a severe hypertriglyceridemia, a formerly unknown 24 nucleotide deletion in exon 2 of the APOA5 gene was detected. The homozygous mutation results in an eight amino acid loss in the signal peptide sequence (c.16_39del; p.Ala6_Ala13del). Screening of control persons proved that this deletion is a rare mutation. Hypertriglyceridemia in the patient was only found at the time when he was breast fed, while after weaning, triglyceride levels were close to normal. Under both dietary conditions, apoA-V protein was undetectable in plasma while post-heparin plasma lipoprotein lipase activity was normal. Expression analysis of normal and mutated protein by Western blot and immunofluorescence in apoA-V deficient primary hepatocytes revealed that, due to changes in the signal peptide, mutated apoA-V was intracellularly missorted to lipid droplets and not secreted. Wild type apoA-V, instead, was not targeted to lipid droplets but transported via endosomal compartments to the plasma membrane for secretion. It is concluded that the c.16_39del mutation in the APOA5 gene leads to hepatic missorting and impaired secretion, which consequently results in undetectable apoA-V plasma levels. The absence of apoA-V in plasma leads under conditions of fat-rich diets to severe chylomicronemia, suggestive for a modulatory role of apoA-V for lipoprotein lipase mediated intravascular triglyceride lipolysis.
authors: Department of Biochemistry and Molecular Biology II, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors: Kirstin
authors: K
authors: Albers
authors: Department of Biochemistry and Molecular Biology II, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors: Christian
authors: C
authors: Schlein
authors: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors: Kirsten
authors: K
authors: Wenner
authors: Department of Clinical Chemistry - Großhadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377 München, Germany.
authors: Peter
authors: P
authors: Lohse
authors: Department of Biochemistry and Molecular Biology II, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors: Alexander
authors: A
authors: Bartelt
authors: Department of Biochemistry and Molecular Biology II, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors: Joerg
authors: J
authors: Heeren
authors: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors: René
authors: R
authors: Santer
authors: Department of Medicine, Asklepios Clinic St. Georg, Lohmuehlenstr. 5, 20099 Hamburg, Germany. Electronic address: m.merkel@asklepios.com.
authors: Martin
authors: M
authors: Merkel
mesh_terms: D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001942:Breast Feeding; D002914:Chylomicrons / Q000097:blood*; D003241:Consanguinity; D006720:Homozygote; D006801:Humans; D007223:Infant; D008099:Liver / Q000378:metabolism; D008297:Male; D021382:Protein Sorting Signals / Q000235:genetics; D017384:Sequence Deletion
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D002914:Chylomicrons; D021382:Protein Sorting Signals
keywords: APOA5; ApoA-V; Apolipoprotein A-V; Chylomicronemia; Deletion; Hypertriglyceridemia; Mutation; Signal peptide; Triglyceride