Abstract
Dominantly inherited familial amyloidosis, Finnish type (FAF) is caused by the accumulation of a 71–amino acid amyloidogenic fragment of mutant gelsolin (GSN). FAF is common in Finland but is very rare elsewhere. In Finland and in two American families, the mutation is a G654A transition leading to an Asp to Asn substitution at residue 187. We found the same mutation in a Dutch family but a Danish FAF family had a G654T mutation, predicting Asp to Tyr at residue 187. We also found the G654T transversion in a Czech family. Using GSN polymorphisms, different haplotypes were found in the Danish and Czech families. We conclude that substitution of the uncharged Asn or Tyr for the acidic Asp at residue 187 creates a conformation that may be preferentially amyloidogenic for GSN.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Benson, M.D. & Wallace, M.R. Amyloidosis. In The metabolic basis of inherited disease 2439–2460 (McGraw-Hill, New York, 1989).
Benson, M.D. Inherited amyloidosis. J. med. Genet. 28, 73–78 (1991).
Tanzi, R.E. Invited Editorial: Gene mutations in inherited amyloidopathies of the nervous system. Am. J. hum. Genet. 49, 507–510 (1991).
McKusick, V.A. Mendelian Inheritance in Man 9th edn 58–59 (Johns Hopkins University Press, Baltimore, 1990).
Meretoja, J. Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms. Ann. clin. Res. 1, 314–324 (1969).
Meretoja, J. Tautiperintöämme: suomalainen amyloiditauti. J. Finn. med. Assoc. 31, 2234–2236 (1976).
Winkelman, J.E., Delleman, J.W. & Ansink, J.J. Ein hereditäres Syndrom, bestehend aus peripherer Polyneuropathie, Hautveränderungen und gittriger Dystrophie der Hornhaut. Klin. Monatsbl. Augenheilk. 159, 618–623 (1971).
Donders, P.C. & Blanksma, L.J. Meretoja syndrome. Lattice dystrophy of the cornea with hereditary generalized amyloidosis. Ophthalmologica 178, 173–180 (1979).
Boysen, G., Galassi, G., Kamieniecka, Z., Schlaeger, J. & Trojaborg, W. Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy. J. Neurol. neurosurg. Psychiatry 42, 1020–1030 (1979).
Sack, G.H., Jr., Dumars, K.W., Gummerson, K.S., Law, A. & McKusick, V.A. Three forms of dominant amyloid neuropathy. Johns Hopkins med. J. 149, 239–247 (1981).
Purcell, J.J., Jr., Rodrigues, M., Chishti, M.I., Riner, R.N. & Dooley, J.M. Lattice corneal dystrophy associated with familial systemic amyloidosis (Meretoja's syndrome). Ophthalmology 90, 1512–1517 (1983).
Darras, B.T., Adelman, L.S., Mora, J.S., Rodzinger, R.A. & Munsat, T.L. Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy. Neurology 36, 432–435 (1986).
Starck, T. et al. Clinical and histopathologic studies of two families with lattice corneal dystrophy and familial systemic amyloidosis (Meretoja syndrome). Ophthalmology 98, 1197–1209 (1991).
Klaus, E., Freyberger, E., Kavka, G. & Vodicka, F. Familiäres Vorkommen von bulbärparalytischer Form der amyotrophischen Lateralsklerose mit gittriger Hornhautdystrophie und Cutis hyperelastica bei drei Schwestern. Psychiat. Neurol. 138, 79–97 (1959).
Vrabec, F. Étude neurohistologique d'un cas de dystrophie grillagëe de la cornée. Ophthalmologica 133, 160–169 (1957).
Maury, C.P.J., Alli, K. & Baumann, M. Finnish hereditary amyloidosis. Amino acid sequence homology between the amyloid fibril protein and human plasma gelsoline. FEBS Lett. 260, 85–87 (1990).
Maury, C.P.J. & Baumann, M. Isolation and characterization of cardiac amyloid in familial amyloid polyneuropathy type IV (Finnish): relation of the amyloid protein to variant gelsolin. Biochim. Biophys. Acta 1096, 84–86 (1990).
Ghiso, J., Haltia, M., Prelli, F., Novello, J. & Frangione, G. Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type. Biochem. J. 272, 827–830 (1990).
Maury, C.P.J. Gelsolin-related amyloidosis. Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin. J. clin. Invest. 87, 1195–1199 (1991).
Maury, C.P.J., Kere, J., Tolvanen, R. & de la Chapelle, A. Finnish hereditary amyloidosis caused by a single nucleotide substitution in the gelsolin gene. FEBS Lett. 276, 75–77 (1990).
Levy, E. et al. Mutation in gelsolin gene in Finnish hereditary amyloidosis. J. exp. Med. 172, 1865–1867 (1990).
Kwiatkowski, D.J., Mehl, R. & Yin, H.L. et al. Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain. Nature 323, 455–458 (1986).
Kwiatkowski, D.J., Mehl, R. & Yin, H.L. Genomic organization and biosynthesis of secreted and cytoplasmic forms of gelsolin. J. Cell Biol. 106, 375–384 (1988).
Gorevic, P.D. et al. Amyloidosis due to a mutation of the gelsolin gene in an American family with lattice corneal dystrophy type II. New Engl. J. Med. 325, 1780–1785 (1991).
de la Chapelle, A., Kere, J., Sack, G.H. Jr., Tolvanen, R. & Maury, C. P. J. Familial Amyloidosis, Finnish type: G654 to A mutation of the gelsolin gene in Finnish families and an unrelated American family. Genomics 13, 898–901 (1992).
Hiltunen, T. et al. Finnish Type of Familial Amyloidosis: Cosegregation of Asp187 to Asn mutation of gelsolin with disease in three large families. Am. J. hum. Genet. 49, 523–528 (1991).
Paunio, T. et al. Solid-phase minisequencing test reveals Asp187 to Asn (G654 to A) mutation of gelsolin in all affected individuals with Finnish type of familial amyloidosis. Genomics 13, 237–239 (1992).
Maury, C.P.J., Kere, J., Tolvanen, R. & de la Chapelle, A. Homozygosity for the ASN187 gelsolin mutation in Finnish-type familial amyloidosis is associated with severe renal disease. Genomics 13, 902–903 (1992).
Kwiatkowski, D.J., Schuback, D., Ozelius, L.,, Gusella, J., Breakefield, X. O. The gelsolin (GSN) cDNA clone, from 9q32-34, identifies Bell and Stul RFLPs. Nucl. Adds Res. 17, 4425 (1989).
Way, M. & Weeds, A. Nucleotide sequence of pig plasma gelsolin: comparison of protein sequence with human gelsolin and other actin-severing proteins shows strong homologies and evidence for large internal repeats. J. molec. Biol. 203, 1127–1133 (1988).
Chou, P.Y. & Fasman, G.D. Prediction of the secondary structure of proteins from their amino acid sequence. Adv. Enzym. 47, 45–147 (1978).
Garnier, J., Osguthorpe, D.J. & Robson, B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J. molec. Biol. 120, 97–120 (1978).
Devereux, J., Haeberli, P. & Smithies, O. A comprehensive set of sequence analysis programs for the VAX. Nucl. Acids Res. 12, 387–395 (1984).
Maury, C.P.J. & Nurmiaho-Lassila, E.-L. Creation of amyloid fibrils from mutant ASN 187 gelsolin peptides. Biochem. Biophys. Res. Commun. 183, 227–231 (1992).
Goate, A.M. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).
Murrell, J., Farlow, M., Ghetti, B. & Benson, M.D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254, 97–99 (1991).
Chartier-Harlin, M.-C. et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–845 (1991).
Hendriks, L. et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nature Genet. 1, 218–221 (1992).
Mullan, M. et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid. Nature Genet. 1, 345–347 (1992).
St George-Hyslop, P.H. et al. Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder. Nature 347, 194–197 (1990).
Schellenberg, G.D. et al. Linkage analysis of familial Alzheimer disease, using chromosome 21 markers. Am. J. hum. Genet. 48, 563–583 (1991).
Levy, E. et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).
Bakker, E. et al. DNA diagnosis for hereditary cerebral hemorrage with amyloidosis (Dutch type). Am. J. hum. Genet. 49, 518–521 (1991).
Srivastava, A.K., Montanaro, V. & Kere, J. Simplified template preparation and improved direct sequencing using Taq polymerase. PCR Methods and Applic. 1, 255–256 (1992).
Kwiatkowski, D.J. & Perman, S. Dinucleotide repeat polymorphism at the GSN locus (9q32–34). Nucl. Acids Res. 19, 967 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
de la Chapelle, A., Tolvanen, R., Boysen, G. et al. Gelsolin–derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187. Nat Genet 2, 157–160 (1992). https://doi.org/10.1038/ng1092-157
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1092-157
This article is cited by
-
Finnish gelsolin amyloidosis causes significant disease burden but does not affect survival: FIN-GAR phase II study
Orphanet Journal of Rare Diseases (2020)
-
The structure of N184K amyloidogenic variant of gelsolin highlights the role of the H-bond network for protein stability and aggregation properties
European Biophysics Journal (2020)
-
Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy
Acta Neuropathologica Communications (2019)
-
Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease
Nature Reviews Neurology (2019)
-
The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray
Molecular Genetics and Genomics (2019)