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. 1993 Oct;53(4):822–827.

Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): codon 178 mutation and codon 129 polymorphism.

R Medori 1, H J Tritschler 1
PMCID: PMC1682394  PMID: 8105681

Abstract

Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp)-->AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. We confirmed the 178Asn mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologic findings associated with 178Asn reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129Met/Val. Moreover, of five 178Asn individuals who are above age-at-onset range and who are well, two have 129Met and three have 129Met/Val, suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178Asn mutation.

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Selected References

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

  1. Asher J. H., Jr, Friedman T. B. Mouse and hamster mutants as models for Waardenburg syndromes in humans. J Med Genet. 1990 Oct;27(10):618–626. doi: 10.1136/jmg.27.10.618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baker H. E., Poulter M., Crow T. J., Frith C. D., Lofthouse R., Ridley R. M. Aminoacid polymorphism in human prion protein and age at death in inherited prion disease. Lancet. 1991 May 25;337(8752):1286–1286. doi: 10.1016/0140-6736(91)92953-y. [DOI] [PubMed] [Google Scholar]
  3. Brown P., Goldfarb L. G., Kovanen J., Haltia M., Cathala F., Sulima M., Gibbs C. J., Jr, Gajdusek D. C. Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178Asn PRNP mutation. Ann Neurol. 1992 Mar;31(3):282–285. doi: 10.1002/ana.410310309. [DOI] [PubMed] [Google Scholar]
  4. Brown P. The phenotypic expression of different mutations in transmissible human spongiform encephalopathy. Rev Neurol (Paris) 1992;148(5):317–327. [PubMed] [Google Scholar]
  5. Buge A., Escourolle R., Brion S., Rancurel G., Hauw J. J., Mehaut M., Gray F., Gajdusek D. C. Maladie de Creutzfeldt-Jakob familiale. Etude clinique et anatomique de trois cas sur huit répartis sur trois générations. Transmission au singe écureuil. Rev Neurol (Paris) 1978 Mar;134(3):165–181. [PubMed] [Google Scholar]
  6. Cathala F., Brown P., Chatelain J., Castaigne P., Gajdusek C. Maladie de Creutzfeldt-Jakob en France. Intérêt des formes familiales. Existe-t-il un gène gouvernant la durée de l'incubation? Presse Med. 1986 Feb 22;15(8):379–382. [PubMed] [Google Scholar]
  7. Collinge J., Owen F., Poulter M., Leach M., Crow T. J., Rossor M. N., Hardy J., Mullan M. J., Janota I., Lantos P. L. Prion dementia without characteristic pathology. Lancet. 1990 Jul 7;336(8706):7–9. doi: 10.1016/0140-6736(90)91518-f. [DOI] [PubMed] [Google Scholar]
  8. Collinge J., Palmer M. S., Dryden A. J. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet. 1991 Jun 15;337(8755):1441–1442. doi: 10.1016/0140-6736(91)93128-v. [DOI] [PubMed] [Google Scholar]
  9. Doh-ura K., Tateishi J., Sasaki H., Kitamoto T., Sakaki Y. Pro----leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Sträussler syndrome. Biochem Biophys Res Commun. 1989 Sep 15;163(2):974–979. doi: 10.1016/0006-291x(89)92317-6. [DOI] [PubMed] [Google Scholar]
  10. FRIEDE R. L., DEJONG R. N. NEURONAL ENZYMATIC FAILURE IN CREUTZFELDT-JAKOB DISEASE; A FAMILIAL STUDY. Arch Neurol. 1964 Feb;10:181–195. doi: 10.1001/archneur.1964.00460140067009. [DOI] [PubMed] [Google Scholar]
  11. Goldfarb L. G., Brown P., Haltia M., Cathala F., McCombie W. R., Kovanen J., Cervenáková L., Goldin L., Nieto A., Godec M. S. Creutzfeldt-Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin. Ann Neurol. 1992 Mar;31(3):274–281. doi: 10.1002/ana.410310308. [DOI] [PubMed] [Google Scholar]
  12. Goldfarb L. G., Haltia M., Brown P., Nieto A., Kovanen J., McCombie W. R., Trapp S., Gajdusek D. C. New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish Creutzfeldt-Jakob kindred. Lancet. 1991 Feb 16;337(8738):425–425. doi: 10.1016/0140-6736(91)91198-4. [DOI] [PubMed] [Google Scholar]
  13. Goldfarb L. G., Petersen R. B., Tabaton M., Brown P., LeBlanc A. C., Montagna P., Cortelli P., Julien J., Vital C., Pendelbury W. W. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science. 1992 Oct 30;258(5083):806–808. doi: 10.1126/science.1439789. [DOI] [PubMed] [Google Scholar]
  14. Goldgaber D., Goldfarb L. G., Brown P., Asher D. M., Brown W. T., Lin S., Teener J. W., Feinstone S. M., Rubenstein R., Kascsak R. J. Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome. Exp Neurol. 1989 Nov;106(2):204–206. doi: 10.1016/0014-4886(89)90095-2. [DOI] [PubMed] [Google Scholar]
  15. Haltia M., Kovanen J., Van Crevel H., Bots G. T., Stefanko S. Familial Creutzfeldt-Jakob disease. J Neurol Sci. 1979 Aug;42(3):381–389. doi: 10.1016/0022-510x(79)90171-0. [DOI] [PubMed] [Google Scholar]
  16. Hsiao K., Baker H. F., Crow T. J., Poulter M., Owen F., Terwilliger J. D., Westaway D., Ott J., Prusiner S. B. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. 1989 Mar 23;338(6213):342–345. doi: 10.1038/338342a0. [DOI] [PubMed] [Google Scholar]
  17. Hsiao K., Dlouhy S. R., Farlow M. R., Cass C., Da Costa M., Conneally P. M., Hodes M. E., Ghetti B., Prusiner S. B. Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Nat Genet. 1992 Apr;1(1):68–71. doi: 10.1038/ng0492-68. [DOI] [PubMed] [Google Scholar]
  18. Julien J., Vital C., Deleplanque B., Lagueny A., Ferrer X. Atrophie thalamique subaiguë familiale. Troubles mnésiques et insomnie totale. Rev Neurol (Paris) 1990;146(3):173–178. [PubMed] [Google Scholar]
  19. Lugaresi E., Medori R., Montagna P., Baruzzi A., Cortelli P., Lugaresi A., Tinuper P., Zucconi M., Gambetti P. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med. 1986 Oct 16;315(16):997–1003. doi: 10.1056/NEJM198610163151605. [DOI] [PubMed] [Google Scholar]
  20. Manetto V., Medori R., Cortelli P., Montagna P., Tinuper P., Baruzzi A., Rancurel G., Hauw J. J., Vanderhaeghen J. J., Mailleux P. Fatal familial insomnia: clinical and pathologic study of five new cases. Neurology. 1992 Feb;42(2):312–319. doi: 10.1212/wnl.42.2.312. [DOI] [PubMed] [Google Scholar]
  21. Masters C. L., Gajdusek D. C., Gibbs C. J., Jr The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain. 1981 Sep;104(3):535–558. doi: 10.1093/brain/104.3.535. [DOI] [PubMed] [Google Scholar]
  22. May W. W., Itabashi H. H., De Jong R. N. Creutzfeldt-Jakob disease. II. Clinical, pathologic, and genetic study of a family. Arch Neurol. 1968 Aug;19(2):137–149. doi: 10.1001/archneur.1968.00480020023002. [DOI] [PubMed] [Google Scholar]
  23. Medori R., Montagna P., Tritschler H. J., LeBlanc A., Cortelli P., Tinuper P., Lugaresi E., Gambetti P. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology. 1992 Mar;42(3 Pt 1):669–670. doi: 10.1212/wnl.42.3.669. [DOI] [PubMed] [Google Scholar]
  24. Medori R., Tritschler H. J., Gambetti P. Production of single-stranded DNA for sequencing: an alternative approach. Biotechniques. 1992 Mar;12(3):346–350. [PubMed] [Google Scholar]
  25. Medori R., Tritschler H. J., LeBlanc A., Villare F., Manetto V., Chen H. Y., Xue R., Leal S., Montagna P., Cortelli P. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med. 1992 Feb 13;326(7):444–449. doi: 10.1056/NEJM199202133260704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nieto A., Goldfarb L. G., Brown P., McCombie W. R., Trapp S., Asher D. M., Gajdusek D. C. Codon 178 mutation in ethnically diverse Creutzfeldt-Jakob disease families. Lancet. 1991 Mar 9;337(8741):622–623. doi: 10.1016/0140-6736(91)91696-r. [DOI] [PubMed] [Google Scholar]
  27. Owen F., Poulter M., Collinge J., Crow T. J. Codon 129 changes in the prion protein gene in Caucasians. Am J Hum Genet. 1990 Jun;46(6):1215–1216. [PMC free article] [PubMed] [Google Scholar]
  28. Owen F., Poulter M., Collinge J., Leach M., Shah T., Lofthouse R., Chen Y. F., Crow T. J., Harding A. E., Hardy J. Insertions in the prion protein gene in atypical dementias. Exp Neurol. 1991 May;112(2):240–242. doi: 10.1016/0014-4886(91)90075-n. [DOI] [PubMed] [Google Scholar]
  29. Palmer M. S., Dryden A. J., Hughes J. T., Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature. 1991 Jul 25;352(6333):340–342. doi: 10.1038/352340a0. [DOI] [PubMed] [Google Scholar]
  30. Prusiner S. B. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515–1522. doi: 10.1126/science.1675487. [DOI] [PubMed] [Google Scholar]
  31. Willems P. J., Garcia C. A., De Smedt M. C., Martin-Jimenez R., Darby J. K., Duenas D. A., Granado-Villar D., O'Brien J. S. Intrafamilial variability in fucosidosis. Clin Genet. 1988 Jul;34(1):7–14. doi: 10.1111/j.1399-0004.1988.tb02608.x. [DOI] [PubMed] [Google Scholar]

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