Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Abstract

The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Amyloidosis is a rare disorder characterized by extracellular deposition of fibrillar protein that results in a progressive disruption of structure and function of affected tissues and organs. Amyloidosis is a remarkably heterogeneous disease; it can be acquired or hereditary and systemic or localized.The most common form of systemic amyloidosis is AL (light chain, previously referred to as "primary"), in which the fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (V L ) domain. The prognosis of systemic AL amyloidosis is generally worse than in other amyloid types, although there is marked heterogeneity in the extent of organ involvement and rate of disease progression. Treatment of AL amyloidosis is with chemotherapy for which there is no role in other amyloid types.Hereditary systemic amyloidosis is a rare autosomal dominant condition caused by deposition of variant proteins as amyloid fibrils. The term "hereditary nonneuropathic systemic amyloidosis" (Online Mendelian Inheritance of Man no. 105200) was coined by Ostertag 1 in 1932 following the discovery of two families with dominantly inherited renal amyloidosis. Mutations in the genes encoding apolipoprotein A-I (apoAI), 2-12 apolipoprotein A-II (apoAII), 13 fibrinogen A␣-chain, 14 -17 and lysozyme 18 have since been identified as the cause of hereditary renal amyloidosis in different kindreds (Online Mendelian Inheritance of Man no. 105200). The clinical amyloidosis syndromes that accompany the various mutations in these different genes are diverse with respect to age at onset, mode of presentation, pattern of organ distribution, rate of progression, and prognosis. Indeed, certain apoAI variants are associated with neuropathy 19,20 such that the nomenclature, which includes the term "nonneuropathic," is confusing and probably no longer appropriate.Supported by the UK Department of Health.Accepted for publication June 15, 2011.The licensed patent rights to perform protein extraction from paraffinembedded tissue for the mass spectrometry-based amyloid typing test were granted by Expression Patholo...

Renal ApoA-1 Amyloidosis with Glu34Lys Mutation and Intra-amyloid Lipid Accumulation

“…3 More than 50 natural variants of ApoA-I have been described, and a little over one third are associated with familial amyloidosis, with 19 known mutations in the APOA1 gene. 2,[4][5][6][7][8][9] Eriksson et al have described different patterns of organ involvement by hereditary ApoA-1 amyloidosis based on specific mutations in hot-spot regions of the APOA1 gene: Mutations in coding regions 50-93 were more likely to cause hepatic and renal involvement, whereas mutations in regions 173-178 were more prone to cardiac, laryngeal, and cutaneous involvement. 10 In addition, the peptide comprising residues 46-59 forms amyloidlike fibrils, and researchers have suggested that this region is responsible for selfrecognition, aggregation, and overall amylogenic propensity of ApoA-1 amyloid.…”

Dual Role of an N-terminal Amyloidogenic Mutation in Apolipoprotein A-I

“…It is known that apoA-I amyloid fibrils extracted from patients with hereditary apoA-I amyloidosis consist of the N-terminal 9 -11-kDa fragments; the fibrillar deposits in the heart contain mainly the 1-93 fragment, whereas those in other organs contain fragments ranging from approximately residues 1-80 to 1-100 (12,13). In the Iowa (G26R) mutation, the major protein constituent of the fibrils isolated from spleen and liver was found to be residues 1-83 of apoA-I (21).…”

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

“…So far, there are about 20 known mutations in the APOA1 gene associated with hereditary systemic apoA-I amyloidosis (9,10), among which G26R, the first and most common amyloidogenic mutation (11)(12)(13), is characterized by amyloid deposits in the peripheral nerves, kidneys, liver, and gastrointestinal tract (11,14). Although the precise mechanism for the amyloidogenicity of variant apoA-I remains unclear, it is thought that an unstable N-terminal helix bundle conformation associated with amyloidogenic mutations promotes proteolytic cleavage of the full-length protein (10,15,16), which deposits in the extracellular space of target tissues (17).…”