Hereditary Renal Amyloidosis Associated With a Novel Apolipoprotein A-II Variant

To the Editor: Systemic amyloidosis is characterized by the extracellular deposition of misfolded proteins as insoluble amyloid fibrils in various tissues. The familial forms of amyloidosis (AF) comprise a group of autosomal dominant diseases associated with mutations in a number of genes encoding amyloid precursor proteins. These diseases collectively exhibit various phenotypes, including ages of onset, organ involvements, rates of progression, and prognoses. Hereditary nonneuropathic, renal amyloidosis was first reported by Ostertag; since that report, mutations in lysozyme, fibrinogen A-a chain, transthyretin, gelsolin, apolipoprotein (apo) A-I, A-II, A-IV, C-II, and C-III have been linked to the disease. apoA-II Amyloidosis (AApoAII) is an exceedingly rare form of AF; only 3 APOA2 mutations have been reported in 4 families worldwide. In each case, a nucleotide replacement at the stop codon of APOA2 resulted in a variant apoA-II with a 21-residue C-terminal extension, 78Argext21, 78Serext21, and 78Glyext21. Human apoA-II (77 amino acids, 17 kDa) is expressed in the liver and is found as a disulfide-linked homodimer in circulation. Nearly all circulatingwild-type apoA-II is strongly bound to plasma high-density lipoprotein (HDL) via the unusually large apolar faces of its amphipathic a-helices. Similar to other exchangeable apolipoproteins, lipid-bound apoA-II acquires a highly a-helical structure on HDL. Strong binding to HDL makes wild-type apoA-II practically nonexchangeable and protected frommisfolding in vivo. However, in the absence of bound lipids in vitro, apoA-II becomes largely unfolded and labile to misfolding and proteolysis. Therefore, a population shift from HDL-bound to HDL-unbound apolipoprotein is thought to augment the development of AApoAII amyloidosis. Notably, apoA-II is the most hydrophobic member of the apolipoprotein family with the highest predicted propensity to form amyloid. Here, we report a family with renal amyloidosis associated with a novel stop codon mutation in APOA2 and the apoA-II variant, 78Leuext21.