Advertisement

New clinical forms of hereditary apoA-I amyloidosis entail both glomerular and retinal amyloidosis

Published:April 23, 2020DOI:https://doi.org/10.1016/j.kint.2020.03.033
      Apolipoprotein A1 amyloidosis (ApoAI) results from specific mutations in the APOA1 gene causing abnormal accumulation of amyloid fibrils in diverse tissues. The kidney is a prominent target tissue in ApoAI amyloidosis with a remarkable selectivity for the renal medulla. Here, we investigated six French families with ApoAI Glu34Lys, p.His179Profs∗47, and a novel p.Thr185Alafs∗41 variant revealing unprecedented clinical association of a glomerular with a retinal disease. Comprehensive clinicopathological, molecular and proteomics studies of numerous affected tissues ensured the correlation between clinical manifestations, including novel unrecognized phenotypes, and apoA-I amyloid deposition. These ophthalmic manifestations stemmed from apoA-I amyloid deposition, highlighting that the retina is a previously unrecognized tissue affected by ApoAI amyloidosis. Our study provides the first molecular evidence that a significant fraction of ApoAI amyloidosis cases with no family history result from spontaneous neomutations rather than variable disease penetrance. Finally, successful hepatorenal transplantation resulted in a life- and vision-saving measure for a 32-year-old man with a hitherto unreported severe ApoAI amyloidosis caused by the very rare Glu34Lys variant. Our findings reveal new modes of occurrence and expand the clinical spectrum of ApoAI amyloidosis. The awareness of glomerular and ocular manifestations in ApoAI amyloidosis should enable earlier diagnosis and avoid misdiagnosis with other forms of renal amyloidosis. Thus, documented apoA-I amyloid deposition in the retina offers new biological information about this disease and may change organ transplantation practice to reduce retinal damage in patients with ApoAI amyloidosis.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment
      ISN Member Login
      Login with your ISN username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rosenson R.S.
        • Brewer Jr., H.B.
        • Davidson W.S.
        • et al.
        Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
        Circulation. 2012; 125: 1905-1919
        • Sorci-Thomas M.G.
        • Thomas M.J.
        The effects of altered apolipoprotein A-I structure on plasma HDL concentration.
        Trends Cardiovasc Med. 2002; 12: 121-128
        • Nichols W.C.
        • Dwulet F.E.
        • Liepnieks J.
        • et al.
        Variant apolipoprotein AI as a major constituent of a human hereditary amyloid.
        Biochem Biophys Res Commun. 1988; 156: 762-768
        • Obici L.
        • Bellotti V.
        • Mangione P.
        • et al.
        The new apolipoprotein A-I variant leu(174) → Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93-residue N-terminal polypeptide.
        Am J Pathol. 1999; 155: 695-702
        • Gursky O.
        • Mei X.
        • Atkinson D.
        The crystal structure of the C-terminal truncated apolipoprotein A-I sheds new light on amyloid formation by the N-terminal fragment.
        Biochemistry. 2012; 51: 10-18
        • Das M.
        • Wilson C.J.
        • Mei X.
        • et al.
        Structural stability and local dynamics in disease-causing mutants of human apolipoprotein A-I: what makes the protein amyloidogenic?.
        J Mol Biol. 2016; 428: 449-462
        • Morgado I.
        • Panahi A.
        • Burwash A.G.
        • et al.
        Molecular insights into human hereditary: apolipoprotein A-I amyloidosis caused by the Glu34Lys mutation.
        Biochemistry. 2018; 57: 5738-5747
        • Rowczenio D.M.
        • Noor I.
        • Gillmore J.D.
        • et al.
        Online registry for mutations in hereditary amyloidosis including nomenclature recommendations.
        Hum Mutat. 2014; 35: E2403-E2412
        • Nichols W.C.
        • Gregg R.E.
        • Brewer Jr., H.B.
        • et al.
        A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy.
        Genomics. 1990; 8: 318-323
        • Rowczenio D.
        • Dogan A.
        • Theis J.D.
        • et al.
        Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I.
        Am J Pathol. 2011; 179: 1978-1987
        • Lachmann H.J.
        • Booth D.R.
        • Booth S.E.
        • et al.
        Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.
        N Engl J Med. 2002; 346: 1786-1791
        • Gregorini G.
        • Izzi C.
        • Obici L.
        • et al.
        Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis.
        J Am Soc Nephrol. 2005; 16: 3680-3686
        • Gregorini G.
        • Izzi C.
        • Ravani P.
        • et al.
        Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis.
        Kidney Int. 2015; 87: 1223-1229
        • Traynor C.A.
        • Tighe D.
        • O’Brien F.J.
        • et al.
        Clinical and pathologic characteristics of hereditary apolipoprotein A-I amyloidosis in Ireland.
        Nephrology. 2013; 18: 549-554
        • Eriksson M.
        • Schonland S.
        • Yumlu S.
        • et al.
        Hereditary apolipoprotein AI-associated amyloidosis in surgical pathology specimens: identification of three novel mutations in the APOA1 gene.
        J Mol Diagn. 2009; 11: 257-262
        • Andeen N.K.
        • Lam D.Y.
        • de Boer I.H.
        • Nicosia R.F.
        Renal ApoA-1 amyloidosis with Glu34Lys mutation and intra-amyloid lipid accumulation.
        J Am Soc Nephrol. 2014; 25: 2703-2705
        • Dogan A.
        Amyloidosis: insights from proteomics.
        Annu Rev Pathol. 2017; 12: 277-304
        • Benson M.D.
        • Liepnieks J.
        • Uemichi T.
        • et al.
        Hereditary renal amyloidosis associated with a mutant fibrinogen α-chain.
        Nat Genet. 1993; 3: 252-255
        • Benson M.D.
        • Liepnieks J.J.
        • Yazaki M.
        • et al.
        A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene.
        Genomics. 2001; 72: 272-277
        • Pepys M.B.
        • Hawkins P.N.
        • Booth D.R.
        • et al.
        Human lysozyme gene mutations cause hereditary systemic amyloidosis.
        Nature. 1993; 362: 553-557
        • Levy E.
        • Haltia M.
        • Fernandez-Madrid I.
        • et al.
        Mutation in gelsolin gene in Finnish hereditary amyloidosis.
        J Exp Med. 1990; 172: 1865-1867
        • Efebera Y.A.
        • Sturm A.
        • Baack E.C.
        • et al.
        Novel gelsolin variant as the cause of nephrotic syndrome and renal amyloidosis in a large kindred.
        Amyloid. 2014; 21: 110-112
        • Valleix S.
        • Verona G.
        • Jourde-Chiche N.
        • et al.
        D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile.
        Nat Commun. 2016; 7: 10353
        • Nasr S.H.
        • Dasari S.
        • Hasadsri L.
        • et al.
        Novel type of renal amyloidosis derived from apolipoprotein-CII.
        J Am Soc Nephrol. 2017; 28: 439-445
        • Beirão J.M.
        • Malheiro J.
        • Lemos C.
        • et al.
        Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases.
        Amyloid. 2015; 22: 117-122
        • Reynolds M.M.
        • Veverka K.K.
        • Gertz M.A.
        • et al.
        Ocular manifestations of familial transthyretin amyloidosis.
        Am J Ophthalmol. 2017; 183: 156-162
        • Rousseau A.
        • Terrada C.
        • Touhami S.
        • et al.
        Angiographic signatures of the predominant form of transthyretin amyloidosis (Val30Met mutation).
        Am J Ophthalmol. 2018; 192: 169-177
        • Gillmore J.D.
        • Stangou A.J.
        • Tennent G.A.
        • et al.
        Clinical and biochemical outcome of hepatorenal transplantation for hereditary systemic amyloidosis associated with apolipoprotein Gly26Arg.
        Transplantation. 2001; 71: 986-992
        • Gillmore J.D.
        • Stangou A.J.
        • Lachmann H.J.
        • et al.
        Organ transplantation in hereditary apolipoprotein AI amyloidosis.
        Am J Transplant. 2006; 6: 2342-2347
        • Scalvini T.
        • Martini P.R.
        • Gambera A.
        • et al.
        Spermatogenic and steroidogenic impairment of the testicle characterizes the hereditary leucine-75-proline apolipoprotein A-I amyloidosis.
        J Clin Endocrinol Metab. 2008; 93: 1850-1853
        • Haase C.L.
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • et al.
        Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach.
        PLoS Genet. 2012; 8e1003063
        • Gillmore J.D.
        • Booth D.R.
        • Rela M.
        • et al.
        Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen α-chain variant in an English family.
        QJM. 2000; 93: 269-275
        • Marchesi M.
        • Parolini C.
        • Valetti C.
        • et al.
        The intracellular quality control system down-regulates the secretion of amyloidogenic apolipoprotein A-I variants: a possible impact on the natural history of the disease.
        Biochim Biophys Acta. 2011; 1812: 87-93
        • Fliesler S.J.
        • Bretillon L.
        The ins and outs of cholesterol in the vertebrate retina.
        J Lipid Res. 2010; 51: 399-413
        • Curcio C.A.
        • Johnson M.
        • Rudolf M.
        • et al.
        The oil spill in ageing Bruch membrane.
        Br Ophthalmol. 2011; 95: 1638-1645
        • Li C.M.
        • Clark M.E.
        • Chimento M.F.
        • et al.
        Apolipoprotein localization in isolated drusen and retinal apolipoprotein gene expression.
        Invest Ophthalmol Vis Sci. 2006; 47: 3119-3128
        • Del Giudice R.
        • Domingo-Espin J.
        • Iacobucci
        • et al.
        Structural determinants in ApoA-I amyloidogenic variants explain improved cholesterol metabolism despite low HDL levels.
        Biochim Biophys Acta Mol Basis Dis. 2017; 1863: 3038-3048
        • Weisgraber K.H.
        • Bersot T.P.
        • Mahley R.W.
        • et al.
        A-IMilano apoprotein: isolation and characterization of a cysteine-containing variant of the A-I protein from human high density lipoproteins.
        J Clin Invest. 1980; 66: 901-907
        • Garnier C.
        • Briki F.
        • Nedelec B.
        • et al.
        VLITL is a major cross-β-sheet signal for fibrinogen A α-chain frameshift variants.
        Blood. 2017; 130: 2799-2807
        • Valleix S.
        • Gillmore J.D.
        • Bridoux F.
        • et al.
        Hereditary systemic amyloidosis due to Asp76Asn β2-microglobulin.
        N Engl J Med. 2012; 366: 2276-2283
        • Sethi S.
        • Vrana J.A.
        • Theis J.D.
        • et al.
        Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis.
        Kidney Int. 2012; 82: 226-234

      Linked Article

      • Novel clinical manifestations and treatment of hereditary apoA-I amyloidosis: when a good protein turns bad
        Kidney InternationalVol. 98Issue 1
        • Preview
          Amyloidoses are life-threatening diseases caused by the deposition of various proteins including apolipoprotein A-I, the major protein of plasma high-density lipoprotein. Timely diagnostics of amyloidoses are crucial for their treatment. Colombat et al. reported novel aspects of the hereditary apolipoprotein A-I amyloidosis, including its unexpected clinical presentation and genetic origins, as well as life- and vision-saving hepatorenal transplantation. This study improves the diagnostics of apolipoprotein A-I amyloidosis, optimizes its treatment, and expands our understanding of the molecular basis of this multipronged disease.
        • Full-Text
        • PDF
      • “Green/apple-green birefringence”: unfit for purpose?
        Kidney InternationalVol. 98Issue 5
        • Preview
          Like most people working on amyloid, Colombat et al.1 report that Congo red–stained amyloid shows “green birefringence” or “apple-green birefringence,” although their figures (5b, 6b, 7b, and 7d–f) show various colors, and in at least two (7e and 7f), green is difficult to see. We wrote to Kidney International in 2012 to point out a similar discrepancy between so-called “apple-green birefringence” and multiple colors in an image.2
        • Full-Text
        • PDF