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J Exp Med. 1989 May 1; 169(5): 1771–1778.
PMCID: PMC2189307

Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases


Cystatin C is an inhibitor of lysosomal cysteine proteases and consists of 120 amino acids. A variant of cystatin C lacking the first NH2- terminal residues and having one amino acid substitution at position 68 forms amyloid deposits mainly in the walls of brain arteries, causing fatal strokes in Icelandic patients with familial cerebral hemorrhage secondary to a form of an autosomal dominant amyloidosis. To understand the molecular basis of the genetic defect, the gene encoding cystatin C was isolated from genomic DNA libraries made from normal tissue and the brain of an Icelandic patient with hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). The data indicate that the cystatin C gene encodes a polypeptide of 146 amino acids, of which the first 26 correspond to a secretory peptide signal sequence. The gene contains two intervening sequences that interrupt the coding region at amino acids 55 and 93. Comparison with genes encoding salivary cystatins and kininogen proteins show sequence homology and conservation of exon- intron structure. Except for a mutation in the second exon (CAG instead of CTG in the normal gene, resulting in the substitution of glutamine for a leucine residue), the gene cloned from the brain of the Icelandic patient is identical to the normal cystatin C gene. Thus, HCHWA-I is the first familial type of amyloidosis related to a point mutation in a gene encoding for an inhibitor. The mutation in the structural gene encoding cystatin C appears to be the primary defect in this inherited disorder causing amyloid fibril formation and accumulation followed by cerebral hemorrhage.

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Selected References

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  • Gudmundsson G, Hallgrímsson J, Jónasson TA, Bjarnason O. Hereditary cerebral haemorrhage with amyloidosis. Brain. 1972;95(2):387–404. [PubMed]
  • Jensson O, Gudmundsson G, Arnason A, Blöndal H, Petursdottir I, Thorsteinsson L, Grubb A, Löfberg H, Cohen D, Frangione B. Hereditary cystatin C (gamma-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage. Acta Neurol Scand. 1987 Aug;76(2):102–114. [PubMed]
  • van Duinen SG, Castaño EM, Prelli F, Bots GT, Luyendijk W, Frangione B. Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5991–5994. [PubMed]
  • Mandybur TI. The incidence of cerebral amyloid angiopathy in Alzheimer's disease. Neurology. 1975 Feb;25(2):120–126. [PubMed]
  • Cohen DH, Feiner H, Jensson O, Frangione B. Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace. J Exp Med. 1983 Aug 1;158(2):623–628. [PMC free article] [PubMed]
  • Barrett AJ, Davies ME, Grubb A. The place of human gamma-trace (cystatin C) amongst the cysteine proteinase inhibitors. Biochem Biophys Res Commun. 1984 Apr 30;120(2):631–636. [PubMed]
  • CLAUSEN J. Proteins in normal cerebrospinal fluid not found in serum. Proc Soc Exp Biol Med. 1961 May;107:170–172. [PubMed]
  • BUTLER EA, FLYNN FV. The occurrence of post-gamma protein in urine: a new protein abnormality. J Clin Pathol. 1961 Mar;14:172–178. [PMC free article] [PubMed]
  • HOCHWALD GM, THORBECKE GJ. Use of an antiserum against cerebrospinal fluid in demonstration of trace proteins in biological fluids. Proc Soc Exp Biol Med. 1962 Jan;109:91–95. [PubMed]
  • Cejka J, Fleischmann LE. Post- -globulin: isolation and physicochemical characterization. Arch Biochem Biophys. 1973 Jul;157(1):168–176. [PubMed]
  • Turk V, Brzin J, Lenarcic B, Locnikar P, Popović T, Ritonja A, Babnik J, Bode W, Machleidt W. Structure and function of lysosomal cysteine proteinases and their protein inhibitors. Prog Clin Biol Res. 1985;180:91–103. [PubMed]
  • Brzin J, Popovic T, Turk V, Borchart U, Machleidt W. Human cystatin, a new protein inhibitor of cysteine proteinases. Biochem Biophys Res Commun. 1984 Jan 13;118(1):103–109. [PubMed]
  • Warfel AH, Zucker-Franklin D, Frangione B, Ghiso J. Constitutive secretion of cystatin C (gamma-trace) by monocytes and macrophages and its downregulation after stimulation. J Exp Med. 1987 Dec 1;166(6):1912–1917. [PMC free article] [PubMed]
  • Müller-Esterl W, Fritz H, Kellermann J, Lottspeich F, Machleidt W, Turk V. Genealogy of mammalian cysteine proteinase inhibitors. Common evolutionary origin of stefins, cystatins and kininogens. FEBS Lett. 1985 Oct 28;191(2):221–226. [PubMed]
  • Salvesen G, Parkes C, Abrahamson M, Grubb A, Barrett AJ. Human low-Mr kininogen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. Biochem J. 1986 Mar 1;234(2):429–434. [PubMed]
  • Ghiso J, Jensson O, Frangione B. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). Proc Natl Acad Sci U S A. 1986 May;83(9):2974–2978. [PubMed]
  • Ghiso J, Cowan N, Frangione B. Isolation of a sequence encoding human cystatin C. Conservation of exon-intron structure between members of the cysteine proteinase inhibitors superfamily. Biol Chem Hoppe Seyler. 1988 May;369 (Suppl):205–208. [PubMed]
  • Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. [PMC free article] [PubMed]
  • Lawn RM, Fritsch EF, Parker RC, Blake G, Maniatis T. The isolation and characterization of linked delta- and beta-globin genes from a cloned library of human DNA. Cell. 1978 Dec;15(4):1157–1174. [PubMed]
  • Benton WD, Davis RW. Screening lambdagt recombinant clones by hybridization to single plaques in situ. Science. 1977 Apr 8;196(4286):180–182. [PubMed]
  • Wallace RB, Shaffer J, Murphy RF, Bonner J, Hirose T, Itakura K. Hybridization of synthetic oligodeoxyribonucleotides to phi chi 174 DNA: the effect of single base pair mismatch. Nucleic Acids Res. 1979 Aug 10;6(11):3543–3557. [PMC free article] [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Lewis SA, Gilmartin ME, Hall JL, Cowan NJ. Three expressed sequences within the human beta-tubulin multigene family each define a distinct isotype. J Mol Biol. 1985 Mar 5;182(1):11–20. [PubMed]
  • Sanger F, Coulson AR, Barrell BG, Smith AJ, Roe BA. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. [PubMed]
  • Tabor S, Richardson CC. DNA sequence analysis with a modified bacteriophage T7 DNA polymerase. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4767–4771. [PubMed]
  • Tsao SG, Brunk CF, Pearlman RE. Hybridization of nucleic acids directly in agarose gels. Anal Biochem. 1983 Jun;131(2):365–372. [PubMed]
  • Watson ME. Compilation of published signal sequences. Nucleic Acids Res. 1984 Jul 11;12(13):5145–5164. [PMC free article] [PubMed]
  • Kozak M. Possible role of flanking nucleotides in recognition of the AUG initiator codon by eukaryotic ribosomes. Nucleic Acids Res. 1981 Oct 24;9(20):5233–5252. [PMC free article] [PubMed]
  • Efstratiadis A, Posakony JW, Maniatis T, Lawn RM, O'Connell C, Spritz RA, DeRiel JK, Forget BG, Weissman SM, Slightom JL, et al. The structure and evolution of the human beta-globin gene family. Cell. 1980 Oct;21(3):653–668. [PubMed]
  • Saitoh E, Kim HS, Smithies O, Maeda N. Human cysteine-proteinase inhibitors: nucleotide sequence analysis of three members of the cystatin gene family. Gene. 1987;61(3):329–338. [PubMed]
  • Dynan WS, Tjian R. Isolation of transcription factors that discriminate between different promoters recognized by RNA polymerase II. Cell. 1983 Mar;32(3):669–680. [PubMed]
  • Basler K, Oesch B, Scott M, Westaway D, Wälchli M, Groth DF, McKinley MP, Prusiner SB, Weissmann C. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell. 1986 Aug 1;46(3):417–428. [PubMed]
  • Cooney M, Czernuszewicz G, Postel EH, Flint SJ, Hogan ME. Site-specific oligonucleotide binding represses transcription of the human c-myc gene in vitro. Science. 1988 Jul 22;241(4864):456–459. [PubMed]
  • Dierks P, van Ooyen A, Cochran MD, Dobkin C, Reiser J, Weissmann C. Three regions upstream from the cap site are required for efficient and accurate transcription of the rabbit beta-globin gene in mouse 3T6 cells. Cell. 1983 Mar;32(3):695–706. [PubMed]
  • Myers RM, Tilly K, Maniatis T. Fine structure genetic analysis of a beta-globin promoter. Science. 1986 May 2;232(4750):613–618. [PubMed]
  • Müller MM, Gerster T, Schaffner W. Enhancer sequences and the regulation of gene transcription. Eur J Biochem. 1988 Oct 1;176(3):485–495. [PubMed]
  • Abrahamson M, Grubb A, Olafsson I, Lundwall A. Molecular cloning and sequence analysis of cDNA coding for the precursor of the human cysteine proteinase inhibitor cystatin C. FEBS Lett. 1987 Jun 1;216(2):229–233. [PubMed]
  • Kitamura N, Kitagawa H, Fukushima D, Takagaki Y, Miyata T, Nakanishi S. Structural organization of the human kininogen gene and a model for its evolution. J Biol Chem. 1985 Jul 15;260(14):8610–8617. [PubMed]
  • Palsdottir A, Abrahamson M, Thorsteinsson L, Arnason A, Olafsson I, Grubb A, Jensson O. Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet. 1988 Sep 10;2(8611):603–604. [PubMed]
  • Al-Hashimi I, Dickinson DP, Levine MJ. Purification, molecular cloning, and sequencing of salivary cystatin SA-1. J Biol Chem. 1988 Jul 5;263(19):9381–9387. [PubMed]
  • Sibanda BL, Thornton JM. Beta-hairpin families in globular proteins. Nature. 1985 Jul 11;316(6024):170–174. [PubMed]

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