A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype

Tougaard, Birgitte Godskesen; Pedersen, Katja Venborg; Krag, Susanne; Gilbertson, Janet A.; Rowczenio, Dorota; Gillmore, Julian D.; Birn, Henrik

doi:10.1016/j.ejmg.2016.05.015

Cited by 17 publications

(16 citation statements)

References 20 publications

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“…Many naturally occurring mutations in human apoA-I are associated with reduced plasma HDL levels and hereditary systemic amyloidosis (3). To date, ϳ20 naturally occurring mutations in human apoA-I associated with familial amyloid polyneuropathy have been reported (4,5) in which the majority of the amyloidogenic mutations are clustered in two regions of the N-terminal residues 26 -90 and 154 -178 (4,6,7). Hereditary apoA-I amyloidosis is characterized by deposition of the N-terminal 80 -100-residue fragments of the variant protein as amyloid fibrils in peripheral organs such as heart, liver, kidneys, or gastrointestinal tract, causing organ damage (6,8,9).…”

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confidence: 99%

Mechanisms of aggregation and fibril formation of the amyloidogenic N-terminal fragment of apolipoprotein A-I

Mizuguchi

Nakagawa

Namba

et al. 2019

Journal of Biological Chemistry

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The N-terminal (1-83) fragment of the major constituent of plasma high-density lipoprotein, apolipoprotein A-I (apoA-I), strongly tends to form amyloid fibrils, leading to systemic amyloidosis. Here, using a series of deletion variants, we examined the roles of two major amyloidogenic segments (residues 14-22 and 50-58) in the aggregation and fibril formation of an amyloidogenic G26R variant of the apoA-I 1-83 fragment (apoA-I 1-83/G26R). Thioflavin T fluorescence assays and atomic force microscopy revealed that elimination of residues 14-22 completely inhibits fibril formation of apoA-I 1-83/G26R, whereas ⌬32-40 and ⌬50-58 variants formed fibrils with markedly reduced nucleation and fibril growth rates. CD measurements revealed structural transitions from random coil to ␤-sheet structures in all deletion variants except for the ⌬14-22 variant, indicating that residues 14-22 are critical for the ␤-transition and fibril formation. Thermodynamic analysis of the kinetics of fibril formation by apoA-I 1-83/G26R indicated that both nucleation and fibril growth are enthalpically unfavorable, whereas entropically, nucleation is favorable, but fibril growth is unfavorable. Interestingly, the nucleation of the ⌬50-58 variant was entropically unfavorable, indicating that residues 50-58 entropically promote the nucleation step in fibril formation of apoA-I 1-83/G26R. Moreover, a residue-level structural investigation of apoA-I 1-83/G26R fibrils with site-specific pyrene labeling indicated that the two amyloidogenic segments are in close proximity to form an amyloid core structure, whereas the N-and C-terminal tail regions are excluded from the amyloid core. These results provide critical insights into the aggregation mechanism and fibril structure of the amyloidogenic N-terminal fragment of apoA-I. Apolipoprotein (apoA-I) 3 is the major structural and functional constituent of plasma high-density lipoprotein (HDL) This work was partly supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant JP17H03979 (to H. S.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S9.

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confidence: 99%

Mechanisms of aggregation and fibril formation of the amyloidogenic N-terminal fragment of apolipoprotein A-I

Mizuguchi

Nakagawa

Namba

et al. 2019

Journal of Biological Chemistry

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“…Acidic intracellular milieu was associated to macrophages activation within inflammatory lesions [40]. As mentioned above, the W50R variant is one of the few exceptions in which apoA-I mutants’ deposits are associated to the glomeruli [13][41]. The extracellular matrix (ECM), especially the proteoglycans (PGs) have diverse biologic functions, including binding of growth factors and regulation of collagen fibrillogenesis [42], and their composition is tissue specific [43].…”

Section: Discussionmentioning

confidence: 99%

“…As a difference from other hereditary amyloidosis, in which renal failure occurs mainly due to glomerular protein deposits [9][10], apoA-I associated disease is mostly characterized by amyloid retention in the medullary interstitium and/or vasculature, which is probably a reason for its misdiagnosis [11][12]. Only rare exceptions were observed within a few mutants including W50R, in which amyloid deposits were found in glomeruli, either confined [13], or expanded to medulla. Previous works from our and other groups have demonstrated that the single point mutations described for apoA-I decrease the marginal protein stability and elicit the tendency to aggregate; even though the conformational shift in the variants is usually subtle under physiological pH and low concentration, it could also induce alterations of the binding to ligands or the eliciting of pro-inflammatory cellular events [14][15].…”

Section: Introductionmentioning

confidence: 99%

N-terminal mutants of human apolipoprotein A-I: structural perturbations associated to protein misfolding

Gisonno

et al. 2019

Preprint

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23Since the early description of different human apolipoprotein A-I variants 24 associated to amyloidosis, the reason that determines its deposition inducing organ 25 failure has been under research. To shed light into the events associated to protein 26 aggregation, we studied the effect of the structural perturbations induced by the 27 replacement of a Leucine in position 60 by an Arginine as it occurs in the natural 28 amyloidogenic variant (L60R). Circular dichroism, intrinsic fluorescence measurements 29 and assays of binding to ligands indicate that L60R is more unstable, more sensitive to 30 proteolysis and interacts with sodium dodecyl sulfate (a model of negative lipids) more 31 than the protein with the native sequence and other natural variant tested, involving a 32 replacement of a Trytophan by and Arginine in the amino acid 50 (W50R). In addition, 33 the small structural rearrangement observed under physiological pH leads to the release 34 of tumor necrosis factor α and interleukin-1β from a model of macrophages. Our results 35 strongly suggest that the chronic disease may be a consequence of the loss in the native 36 conformation which alters the equilibrium among native and cytotoxic proteins 37 conformation. 38 39 40 41 42 Human apolipoprotein A-I (apoA-I) is the main protein associated to high 43 density lipoproteins (HDL). It is synthesized in liver and intestine and both the liver and 44 the kidney are the major sites of its catabolism. Its multiple functions as lipid transport, 45 endothelial homeostasis and inhibition of inflammatory pathways [1][2][3] could 46 however be counter balanced by the presence of single point mutations which could, by 47 not yet completely known pathways, induce its misfunction, increased clearance rate or 48 its tendency to aggregate [4][5]. Hereditary apoA-I amyloidosis has been described 49 since 1969, and is characterized by specific deposits of natural variant proteins within 50 organs, in a pattern which is dependent on the mutation in the protein sequence. From 51 the more than 20 known natural variants, almost half result from substitutions between 52 amino acids 26 and 107, and involve with different severity hepatic and kidney failure.53 Instead, a "hot spot" affecting residues 173-178 was described, in which variants are 54 especially associated to cardiac, skin and testis damage. The reasons for the different 55 deposit patterns are still unknown but may be the consequence of long term seeding of 56 misfolded proteins that yield a final fibrillar conformation. 57 The first identified apoA-I natural mutant was the result of a substitution of a 58 Glycine by an Arginine in position 26 from the native sequence (Gly26Arg, in the 59 abbreviated nomenclature G26R), inducing in patients peripheral neuropathy, peptic 60 ulcer, and nephropathy [6]. The next mutations described in the N terminus of apoA-I 61 were Trp50Arg (W50R) [7] and Leu60Arg (L60R) [8]. These variants show similarities 62 with G26R: in each, a neutral residue is replaced by an Arginine thu...

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“…This is the first report of the mutation in Chinese Han population, and the previous reports were from a Jewish man and a Danish man. [ 5 , 28 ] The major clinical manifestations of the 3 cases include renal amyloidosis and low plasma levels of ApoA-1 and HDL. This may indicate that the Trp74Arg mutation can result in dysfunctional and amyloidogenic ApoA-1 proteins, which mainly targets kidney.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-1-related amyloidosis 2 case reports and review of the literature

Zuo

et al. 2017

Medicine

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Rationale:Apolipoprotein A-1 (ApoA-1)-related amyloidosis is characterized by the deposition of ApoA-1 in various organs and can be either hereditary or nonhereditary. It is rare and easily misdiagnosed. Renal involvement is common in hereditary ApoA-1 amyloidosis, but rare in the nonhereditary form.Patient concerns:We reported two cases with ApoA-1 amyloidosis, a 64-year-old man suffering from nephrotic syndrome and a 40-year-old man with nephrotic syndrome and splenomegaly. Renal biopsies revealed glomerular, interstitial and vascular amyloid deposits and positive phospholipase A2 receptor staining in the glomerular capillary loop in case 1, and mesangial amyloid deposits in case 2.Diagnoses:After immunostaining failed to determine the specific amyloid protein, proteomic analysis of amyloid deposits by mass spectrometry was performed and demonstrated the ApoA-1 origin of the amyloid. Genetic testing revealed no mutation of the APOA1 gene in case 1 but a heterozygous mutation, Trp74Arg, in case 2. Case 1 was thus diagnosed as nonhereditary ApoA-1 associated renal amyloidosis with membranous nephropathy, and case 2 as hereditary ApoA-1 amyloidosis with multiorgan injuries (kidney and spleen) and a positive family history.Interventions:Case 1 was treated with glucocorticoid combined with cyclosporine. Case 2 was treated with calcitriol and angiotensin converting enzyme inhibitors.Outcomes:Two cases were followed up for 5 months and 2 years, respectively; and case 1 was found to have attenuated proteinuria while case 2 had an elevation of cholestasis indices along with renal insufficiency.Lessons:Proteomic analysis by mass spectrometry of the amyloid deposits combined with genetic analysis can provide accurate diagnosis of ApoA-1 amyloidosis. Besides, these 2 cases expand our knowledge of ApoA-1-related renal amyloidosis.

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A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype

Cited by 17 publications

References 20 publications

Mechanisms of aggregation and fibril formation of the amyloidogenic N-terminal fragment of apolipoprotein A-I

Mechanisms of aggregation and fibril formation of the amyloidogenic N-terminal fragment of apolipoprotein A-I

N-terminal mutants of human apolipoprotein A-I: structural perturbations associated to protein misfolding

Apolipoprotein A-1-related amyloidosis 2 case reports and review of the literature

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