Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 15;97(12):2714–2721. doi: 10.1172/JCI118725

Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.

D R Booth 1, S Y Tan 1, S E Booth 1, G A Tennent 1, W L Hutchinson 1, J J Hsuan 1, N F Totty 1, O Truong 1, A K Soutar 1, P N Hawkins 1, M Bruguera 1, J Caballería 1, M Solé 1, J M Campistol 1, M B Pepys 1
PMCID: PMC507363  PMID: 8675681

Abstract

We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.

Full Text

The Full Text of this article is available as a PDF (378.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benson M. D., Liepnieks J., Uemichi T., Wheeler G., Correa R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet. 1993 Mar;3(3):252–255. doi: 10.1038/ng0393-252. [DOI] [PubMed] [Google Scholar]
  2. Booth D. R., Tan S. Y., Booth S. E., Hsuan J. J., Totty N. F., Nguyen O., Hutton T., Vigushin D. M., Tennent G. A., Hutchinson W. L. A new apolipoprotein Al variant, Trp50Arg, causes hereditary amyloidosis. QJM. 1995 Oct;88(10):695–702. [PubMed] [Google Scholar]
  3. Booth D. R., Tan S. Y., Hawkins P. N., Pepys M. B., Frustaci A. A novel variant of transthyretin, 59Thr-->Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation. 1995 Feb 15;91(4):962–967. doi: 10.1161/01.cir.91.4.962. [DOI] [PubMed] [Google Scholar]
  4. Eggerman T. L., Hoeg J. M., Meng M. S., Tombragel A., Bojanovski D., Brewer H. B., Jr Differential tissue-specific expression of human apoA-I and apoA-II. J Lipid Res. 1991 May;32(5):821–828. [PubMed] [Google Scholar]
  5. Glenner G. G. Amyloid deposits and amyloidosis. The beta-fibrilloses (first of two parts). N Engl J Med. 1980 Jun 5;302(23):1283–1292. doi: 10.1056/NEJM198006053022305. [DOI] [PubMed] [Google Scholar]
  6. Hawkins P. N., Lavender J. P., Pepys M. B. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med. 1990 Aug 23;323(8):508–513. doi: 10.1056/NEJM199008233230803. [DOI] [PubMed] [Google Scholar]
  7. Hawkins P. N., Myers M. J., Lavender J. P., Pepys M. B. Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component. Lancet. 1988 Jun 25;1(8600):1413–1418. doi: 10.1016/s0140-6736(88)92235-0. [DOI] [PubMed] [Google Scholar]
  8. Holmgren G., Ericzon B. G., Groth C. G., Steen L., Suhr O., Andersen O., Wallin B. G., Seymour A., Richardson S., Hawkins P. N. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet. 1993 May 1;341(8853):1113–1116. doi: 10.1016/0140-6736(93)93127-m. [DOI] [PubMed] [Google Scholar]
  9. Holmgren G., Steen L., Ekstedt J., Groth C. G., Ericzon B. G., Eriksson S., Andersen O., Karlberg I., Nordén G., Nakazato M. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet. 1991 Sep;40(3):242–246. doi: 10.1111/j.1399-0004.1991.tb03085.x. [DOI] [PubMed] [Google Scholar]
  10. Jensson O., Palsdottir A., Thorsteinsson L., Arnason A. The saga of cystatin C gene mutation causing amyloid angiopathy and brain hemorrhage--clinical genetics in Iceland. Clin Genet. 1989 Nov;36(5):368–377. doi: 10.1111/j.1399-0004.1989.tb03215.x. [DOI] [PubMed] [Google Scholar]
  11. Johnson K. H., Sletten K., Hayden D. W., O'Brien T. D., Roertgen K. E., Westermark P. Pulmonary vascular amyloidosis in aged dogs. A new form of spontaneously occurring amyloidosis derived from apolipoprotein AI. Am J Pathol. 1992 Nov;141(5):1013–1019. [PMC free article] [PubMed] [Google Scholar]
  12. Levy E., Haltia M., Fernandez-Madrid I., Koivunen O., Ghiso J., Prelli F., Frangione B. Mutation in gelsolin gene in Finnish hereditary amyloidosis. J Exp Med. 1990 Dec 1;172(6):1865–1867. doi: 10.1084/jem.172.6.1865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Maury C. P., Kere J., Tolvanen R., de la Chapelle A. Finnish hereditary amyloidosis is caused by a single nucleotide substitution in the gelsolin gene. FEBS Lett. 1990 Dec 10;276(1-2):75–77. doi: 10.1016/0014-5793(90)80510-p. [DOI] [PubMed] [Google Scholar]
  14. Mazière J. C., Myara I., Salmon S., Auclair M., Haigle J., Santus R., Mazière C. Copper- and malondialdehyde-induced modification of high density lipoprotein and parallel loss of lecithin cholesterol acyltransferase activation. Atherosclerosis. 1993 Dec;104(1-2):213–219. doi: 10.1016/0021-9150(93)90192-w. [DOI] [PubMed] [Google Scholar]
  15. Nelson S. R., Lyon M., Gallagher J. T., Johnson E. A., Pepys M. B. Isolation and characterization of the integral glycosaminoglycan constituents of human amyloid A and monoclonal light-chain amyloid fibrils. Biochem J. 1991 Apr 1;275(Pt 1):67–73. doi: 10.1042/bj2750067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nichols W. C., Dwulet F. E., Liepnieks J., Benson M. D. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun. 1988 Oct 31;156(2):762–768. doi: 10.1016/s0006-291x(88)80909-4. [DOI] [PubMed] [Google Scholar]
  17. Nichols W. C., Gregg R. E., Brewer H. B., Jr, Benson M. D. A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy. Genomics. 1990 Oct;8(2):318–323. doi: 10.1016/0888-7543(90)90288-6. [DOI] [PubMed] [Google Scholar]
  18. Parthasarathy S., Barnett J., Fong L. G. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta. 1990 May 22;1044(2):275–283. doi: 10.1016/0005-2760(90)90314-n. [DOI] [PubMed] [Google Scholar]
  19. Pepys M. B., Hawkins P. N., Booth D. R., Vigushin D. M., Tennent G. A., Soutar A. K., Totty N., Nguyen O., Blake C. C., Terry C. J. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature. 1993 Apr 8;362(6420):553–557. doi: 10.1038/362553a0. [DOI] [PubMed] [Google Scholar]
  20. Pepys M. B., Rademacher T. W., Amatayakul-Chantler S., Williams P., Noble G. E., Hutchinson W. L., Hawkins P. N., Nelson S. R., Gallimore J. R., Herbert J. Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5602–5606. doi: 10.1073/pnas.91.12.5602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pras M., Schubert M., Zucker-Franklin D., Rimon A., Franklin E. C. The characterization of soluble amyloid prepared in water. J Clin Invest. 1968 Apr;47(4):924–933. doi: 10.1172/JCI105784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rader D. J., Gregg R. E., Meng M. S., Schaefer J. R., Zech L. A., Benson M. D., Brewer H. B., Jr In vivo metabolism of a mutant apolipoprotein, apoA-IIowa, associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis. J Lipid Res. 1992 May;33(5):755–763. [PubMed] [Google Scholar]
  23. Roertgen K. E., Lund E. M., O'Brien T. D., Westermark P., Hayden D. W., Johnson K. H. Apolipoprotein AI-derived pulmonary vascular amyloid in aged dogs. Am J Pathol. 1995 Nov;147(5):1311–1317. [PMC free article] [PubMed] [Google Scholar]
  24. Selkoe D. J. Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol. 1994 Sep;53(5):438–447. doi: 10.1097/00005072-199409000-00003. [DOI] [PubMed] [Google Scholar]
  25. Selkoe D. J. Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci. 1994;17:489–517. doi: 10.1146/annurev.ne.17.030194.002421. [DOI] [PubMed] [Google Scholar]
  26. Snow A. D., Willmer J., Kisilevsky R. Sulfated glycosaminoglycans: a common constituent of all amyloids? Lab Invest. 1987 Jan;56(1):120–123. [PubMed] [Google Scholar]
  27. Soutar A. K., Hawkins P. N., Vigushin D. M., Tennent G. A., Booth S. E., Hutton T., Nguyen O., Totty N. F., Feest T. G., Hsuan J. J. Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7389–7393. doi: 10.1073/pnas.89.16.7389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tan S. Y., Murdoch I. E., Sullivan T. J., Wright J. E., Truong O., Hsuan J. J., Hawkins P. N., Pepys M. B. Primary localized orbital amyloidosis composed of the immunoglobulin gamma heavy chain CH3 domain. Clin Sci (Lond) 1994 Nov;87(5):487–491. doi: 10.1042/cs0870487. [DOI] [PubMed] [Google Scholar]
  29. Totty N. F., Waterfield M. D., Hsuan J. J. Accelerated high-sensitivity microsequencing of proteins and peptides using a miniature reaction cartridge. Protein Sci. 1992 Sep;1(9):1215–1224. doi: 10.1002/pro.5560010914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Uemichi T., Liepnieks J. J., Benson M. D. Hereditary renal amyloidosis with a novel variant fibrinogen. J Clin Invest. 1994 Feb;93(2):731–736. doi: 10.1172/JCI117027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vigushin D. M., Gough J., Allan D., Alguacil A., Penner B., Pettigrew N. M., Quinonez G., Bernstein K., Booth S. E., Booth D. R. Familial nephropathic systemic amyloidosis caused by apolipoprotein AI variant Arg26. Q J Med. 1994 Mar;87(3):149–154. [PubMed] [Google Scholar]
  32. Wattendorff A. R., Frangione B., Luyendijk W., Bots G. T. Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D): clinicopathological studies. J Neurol Neurosurg Psychiatry. 1995 Jun;58(6):699–705. doi: 10.1136/jnnp.58.6.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Westermark P., Mucchiano G., Marthin T., Johnson K. H., Sletten K. Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques. Am J Pathol. 1995 Nov;147(5):1186–1192. [PMC free article] [PubMed] [Google Scholar]
  34. Wisniewski T., Golabek A. A., Kida E., Wisniewski K. E., Frangione B. Conformational mimicry in Alzheimer's disease. Role of apolipoproteins in amyloidogenesis. Am J Pathol. 1995 Aug;147(2):238–244. [PMC free article] [PubMed] [Google Scholar]
  35. Zannis V. I., Cole F. S., Jackson C. L., Kurnit D. M., Karathanasis S. K. Distribution of apolipoprotein A-I, C-II, C-III, and E mRNA in fetal human tissues. Time-dependent induction of apolipoprotein E mRNA by cultures of human monocyte-macrophages. Biochemistry. 1985 Jul 30;24(16):4450–4455. doi: 10.1021/bi00337a028. [DOI] [PubMed] [Google Scholar]
  36. von Eckardstein A., Walter M., Holz H., Benninghoven A., Assmann G. Site-specific methionine sulfoxide formation is the structural basis of chromatographic heterogeneity of apolipoproteins A-I, C-II, and C-III. J Lipid Res. 1991 Sep;32(9):1465–1476. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES