Novel Type of Renal Amyloidosis Derived from Apolipoprotein-CII

Abstract

Amyloidosis is characterized by extracellular deposition of misfolded proteins as insoluble fibrils. Most renal amyloidosis cases are Ig light chain, AA, or leukocyte chemotactic factor 2 amyloidosis, but rare hereditary forms can also involve the kidneys. Here, we describe the case of a 61-year-old woman who presented with nephrotic syndrome and renal impairment. Examination of the renal biopsy specimen revealed amyloidosis with predominant involvement of glomeruli and medullary interstitium. Proteomic analysis of Congo red-positive deposits detected large amounts of the Apo-CII protein. DNA sequencing of the APOC2 gene in the patient and one of her children detected a heterozygous c.206A→T transition, causing an E69V missense mutation. We also detected the mutant peptide in the proband's renal amyloid deposits. Using proteomics, we identified seven additional elderly patients with Apo-CII-rich amyloid deposits, all of whom had kidney involvement and histologically exhibited nodular glomerular involvement. Although prior in vitro studies have shown that Apo-CII can form amyloid fibrils and that certain mutations in this protein promote amyloid fibrillogenesis, there are no reports of this type of amyloidosis in humans. We propose that this study reveals a new form of hereditary amyloidosis (AApoCII) that is derived from the Apo-CII protein and appears to manifest in the elderly and preferentially affect the kidneys.

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

“…The levels of ApoC-II and ApoC-III are elevated in patients with nephrotic syndrome 40 , although they return to normal within 4 weeks after normalization of the levels of urinary protein, suggesting that the elevated ApoC-II and ApoC-III levels are unlikely to contribute to the development of nephrotic syndrome 41 . However, the finding that ApoC-II may contribute to a new form of amyloidosis that primarily affects the kidney in humans is once more challenging the cause and effect relationship between ApoC-II and nephrotic syndrome 42 . A potential role for ApoA-V in nephrotic syndrome should also be investigated further, as the level of ApoA-V is higher in patients with diabetes and proteinuria than in patients with diabetes without proteinuria 43 .…”

Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines

“…To be included in the official ISA Amyloid Fibril Protein Nomenclature List (Tables 1 and 2), an amyloid fibril protein must have been unambiguously characterized by protein sequence analysis when possible and described in a peer reviewed journal. Two newly recognized fibril proteins, AApoCII derived from apolipoprotein CII [4] and AApoCIII derived from apolipoprotein CIII [5], have been added to Table 1. AApoCII amyloidosis and AApoCIII amyloidosis are rare hereditary systemic amyloidoses.…”

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

“…Protein constituents of these nanoparticles, termed apolipoproteins (apos), form a family of amphipathic lipid surface-binding proteins that are central to cardiovascular health and disease, but are also prominent in amyloid diseases, or amyloidoses ([1-5] and references therein). In amyloidoses, normally soluble functional globular proteins or peptides misfold to form an intermolecular cross-β-sheet and deposit as amyloid fibrils [6].…”