Hostname: page-component-76fb5796d-wq484 Total loading time: 0 Render date: 2024-04-27T03:34:08.062Z Has data issue: false hasContentIssue false
  • English
  • Français

Lack of Association Between Two Restriction Fragment Length Polymorphisms in the Genes for the Light and Heavy Neurofilament Proteins and Alzheimer's Disease

Published online by Cambridge University Press:  18 September 2015

Ginette Lacoste-Royal ,
Martine Mathieu ,
Josephine Nalbantoglu ,
Jean-Pierre Julien ,
Serge Gauthier  and
Denis Gauvreau
Ginette Lacoste-Royal*
Affiliation:
INRS-Santé, Pointe-Claire, Montréal
Martine Mathieu
Affiliation:
INRS-Santé, Pointe-Claire, Montréal
Josephine Nalbantoglu
Affiliation:
INRS-Santé, Pointe-Claire, Montréal
Jean-Pierre Julien
Affiliation:
Institut de Cancer de Montréal, Montréal
Serge Gauthier
Affiliation:
Centre McGill d'études sur le vieillissement, Montréal
Denis Gauvreau
Affiliation:
INRS-Santé, Pointe-Claire, Montréal
*
INRS-Santé, 245 boul. Hymus, Point-Claire, Quebec, Canada H9R 1G6
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The etiology of Alzheimer disease (AD) remains unknown. The hypothesis of genetic factors playing a role in the causation of the disease, at least in its familial form, has been borne out by results showing linkage in several early-onset AD families to a locus on the proximal part of the long arm of chromosome 21. Linkage was not detected in several other families using the same markers. The metabolism of neurofilaments is perturbed in AD, as indicated by the presence of neurofilament epitopes in neurofibrillary tangles, as well as by the severe reduction of the expression of the gene for the light neurofilament subunit in AD brain. To detect a possible anomaly that might relate to the disease, we have searched for an association between the genes for the light subunit and the heavy subunit of the neurofilament triplet, and AD. Genotypes for restriction fragment length polymorphisms (RFLP) at each of the two loci were determined for an AD group and a control group. Allelic frequencies at a Taql-defined RFLP for the gene for the light neurofilament subunit were 0.70 for the 3.7 kb allele and 0.30 for the 2.9 kb allele. Hindi detected an RFLP for the heavy neurofilament subunit gene with frequencies of 0.31 for the 18.0 kb allele and 0.69 for the 6.8 kb allele. Frequencies were found to be similar in the two groups for both light and heavy neurofilament subunit loci. Although it cannot be excluded that mutations at other sites of the neurofilament genes are relevant to AD, the data reported here do not support an association between these genes and the disease.

Résumé:

RÉSUMÉ:

La cause de la maladie d'Alzheimer (MA) demeure inconnue. L'hypothèse que des facteurs génétiques jouent un rôle dans la maladie, du moins dans sa forme familiale, a été confirmée dans un ensemble de quatre familles MA à début précoce, où un linkage a été démontré entre la maladie et un locus situé sur la partie proximale du bras long du chromosome 21. Il n'a pas été possible de déceler ce linkage dans plusieurs autres familles MA, en utilisant les mêmes marqueurs. Le métabolisme des neurofilaments est perturbé dans la MA, comme en témoignent la présence d'épitopes de neurofilaments dans les enchevêtrements neurofibrillaires, et la baisse substantielle d'expression du gène pour la petite sousunité des neurofilaments dans le cerveau affecté par la maladie. Afin de détecter une anomalie possiblement reliée à la MA, nous avons cherché s'il y avait une association entre les gènes pour la petite et la grosse sour-unités des neurofilaments et la MA. Les génotypes pour des polymorphismes dans la taille des fragments de restriction à chacun des deux loci ont été déterminés dans un groupe contrôle et un groupe MA. Les fréquences alléliques pour un polymorphisme Taql dans le gène de la petite sous-unité des neurofilaments sont de 0.7 pour l'allèle de 3.7 kb et 0.3 pour l'allèle de 2.9 kb. HincII détecte un polymorphisme dans le gène de la grosse sous-unité des neurofilaments, avec des fréquences de 0.31 pour l'allèle de 18.0 kb et 0.69 pour l'allèle de 6.8 kb. Les fréquences alléliques sont similaires dans les deux groupes pour les deux loci examinés. Ces résultats ne supportent pas une association entre les gènes des neurofilaments et la MA, quoiqu'on ne puisse exclure une mutation à un autre site.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 17 , Issue 3 , August 1990 , pp. 302 - 305
Copyright
Copyright © Canadian Neurological Sciences Federation 1990

References

REFERENCES

1. Cook, RH, Ward, BE, Austin, H. Studies in aging of the brain: IV. Familial Alzheimer’s disease: relation to transmissable dementia. Neurology 1979; 29: 1402–1412.CrossRefGoogle ScholarPubMed
2. Goudsmit, J, White, BJ, Wietkamp, LR, et al. Familial Alzheimer’s disease in two kindreds of the same geographic and ethnic origin. J Neurol Sci 1981; 49: 79–89.CrossRefGoogle ScholarPubMed
3. Nee, LE, Polinsky, RJ, Eldridge, R, et al. A family with histologically confirmed Alzheimer’s disease. Arch Neurol 1983; 40: 203–208.CrossRefGoogle ScholarPubMed
4. Foncin, JF, Salmon, D, Supino-Viterbo, V, et al. Démence pré-sénile d’Alzheimer transmise dans une famille étendue. Rev Neurol (Paris) 1985; 141: 194–202.Google Scholar
5. Larsson, T, Sjogren, T, Jacobson, G. Senile dementia: a clinical, sociomedical and genetic study. Acta Psychiatr Scand 1963; 39 (Suppl): 167.Google Scholar
6. Heston, LL, Mastri, AR, Anderson, VE, et al. Dementia of the Alzheimer type. Clinical genetics, natural history, and associated conditions. Arch Gen Psychiatry 1981; 38: 1085–1090.CrossRefGoogle ScholarPubMed
7. Soininen, H, Heinonen, OP. Clinical and etiological aspects of senile dementia. Eur Neurol 1982; 21: 401–410.CrossRefGoogle ScholarPubMed
8. Whalley, LJ, Carothers, AD, Collyer, S, et al. A study of familial factors in Alzheimer’s disease. Br J Psychiatry 1982; 140: 249–256.CrossRefGoogle ScholarPubMed
9. Heyman, A, Wilkinson, WE, Hurwitz, BJ, et al. Alzheimer’s disease: Genetic aspects and associated clinical disorders. Ann Neurol 1983; 14: 507–515.CrossRefGoogle ScholarPubMed
10. Amaducci, LA, Fratigliono, L, Rocca, WA, et al. Risk factors for clinically diagnosed Alzheimer’s disease: a case-control study of an Italian population. Neurology 1986; 36: 922–931.CrossRefGoogle ScholarPubMed
11. Breitner, JCS, Folstein, MF. Familial Alzheimer dementia: a prevalent disorder with specific clinical features. Psychol Med 1984; 14: 63–80.CrossRefGoogle ScholarPubMed
12. Fitch, N, Becker, R, Heller, A. The inheritance of Alzheimer’s disease: a new interpretation. Ann Neurol 1988; 23: 14–19.CrossRefGoogle ScholarPubMed
13. Breitner, JCS, Folstein, MF, Murphy, EA. Familial aggregation in Alzheimer dementia-1. A model for the age-dependent expression of an autosomal dominant gene. J Psychiat Res 1986; 20: 31–43.CrossRefGoogle Scholar
14. Nalbantoglu, J, Lacoste-Royal, G, Gauvreau, D. Genetic factors in Alzheimer’s disease. J Am Geriatr Soc (in press).Google Scholar
15. St George-Hyslop, PH, Tanzi, RE, Polinsky, RJ, et al. The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 1987; 235: 885–890.CrossRefGoogle Scholar
16. Goate, AM, Haynes, AR, Owen, MJ, et al. Predisposing locus for Alzheimer’s disease on chromosome 21. Lancet 1989; 1: 352–355.CrossRefGoogle ScholarPubMed
17. Pericak-Vance, MA, Yamaoka, LH, Haynes, CS, et al. Genetic linkage studies in Alzheimer’s disease families. Exp Neurol 1988; 102: 271–279.CrossRefGoogle ScholarPubMed
18. Schellenberg, GD, Bird, TD, Wijsman, EM, et al. Absence of linkage of chromosome 21q21 markers to familial Alzheimer’s disease. Science 1988; 241: 1507–1510.CrossRefGoogle ScholarPubMed
19. van Broeckhoven, C, van Hul, W, Backhovens, W, et al. Genetic linkage analysis in two large Belgian families with chromosome 21 DNA markers. In: Sinet, PM, Lamour, Y, Christen, Y, eds. Genetics and Alzheimer’s disease. Berlin: Springer-Verlag, 1988: 124–129.Google Scholar
20. Selkoe, DJ. Biochemistry of altered brain proteins in Alzheimer’s disease. Ann Rev Neurosci 1989; 12: 463–490.CrossRefGoogle ScholarPubMed
21. Kosik, KS, Joachim, CL, Selkoe, DJ. The microtubule-associated protein, tau, is a major antigenic component of paired helical filaments in Alzheimer’s disease. Proc Natl Acad Sci USA 1986; 83: 4044–4048.CrossRefGoogle Scholar
22. Nukina, N, Ihara, Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem 1986; 99: 1541–1544.CrossRefGoogle ScholarPubMed
23. Wood, JG, Mirra, SS, Pollock, NJ, et al. Neurofibrillary tangles of Alzheimer’s disease share antigenic determinants with the axonal microtubule-associated protein tau. Proc Natl Acad Sci USA 1986; 83: 4040–4043.CrossRefGoogle ScholarPubMed
24. Anderton, BH, Breinburg, D, Downes, MJ, et al. Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature 1982; 298: 84–86.CrossRefGoogle ScholarPubMed
25. Perry, G, Rizzuto, N, Autilio-Gambetti, L, et al. Alzheimer’s paired helical filaments contain cytoskeletal components. Proc Natl Acad Sci USA 1985; 82: 3916–3920.CrossRefGoogle ScholarPubMed
26. Lee, VM-Y, Otvos, L Jr, Schmidt, ML, et al. Alzheimer’s disease tangles share immunological similarities with multiphosphoryla-tion repeats in the two large neurofilament proteins. Proc Natl Acad Sci USA 1988; 85: 7384–7388.CrossRefGoogle ScholarPubMed
27. Sternberger, NH, Sternberger, LA, Ulrich, J. Aberrant neurofilament phosphorylation in Alzheimer’s disease. Proc Natl Acad Sci USA 1985; 82: 4274–4276.CrossRefGoogle Scholar
28. Crapper McLachlan, DR, Lukiw, WJ, Wong, L, et al. Selective messenger RNA reduction in Alzheimer’s disease. Mol Brain Res 1988; 3: 255–262.CrossRefGoogle Scholar
29. Clark, AW, Krekoski, CA, Parhad, IM, et al. Altered expression of genes for amyloid and cytoskeletal proteins in Alzheimer cortex. Ann Neurol 1989; 25: 331–339.CrossRefGoogle ScholarPubMed
30. Julien, J-P, Grosveld, F, Yazdanbaksh, K, et al. The structure of a human neurofilament gene (NF-L): a unique exon-intron organization in the intermediate filament gene family. Biochim Biophys Acta 1987; 909: 10–20.CrossRefGoogle ScholarPubMed
31. Lees, JF, Shneidman, PS, Skuntz, SF, et al. The structure and organization of the human heavy neurofilament subunit (NF-H) and the gene encoding it. The EMBO J 1988; 7: 1947–1955.CrossRefGoogle Scholar
32. Mattei, MG, Dautigny, A, Pham-Dinh, D, et al. The gene encoding the large human neurofilament subunit (NF-H) maps to the q 121 -q 131 region on chromosome 22. Hum Genet 1988; 80: 293–295.CrossRefGoogle Scholar
33. Lieberburg, Y, Spinner, N, Snyder, S, et al. Cloning of a cDNA encoding the rat high molecular weight neurofilament peptide (NF-H): developmental and tissue expression in the rat, and mapping of its human homologue to chromosomes I and 22. Proc Natl Acad Sci USA 1989; 86: 2463–2467.CrossRefGoogle ScholarPubMed
34. McKhann, G, Drachman, D, Folstein, M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984; 34: 939–944.CrossRefGoogle ScholarPubMed
35. Maniatis, T, Fritsch, EF, Sambrook, J. Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1982.Google Scholar
36. Southern, EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 1975; 98: 503–517.CrossRefGoogle ScholarPubMed
37. Feinberg, AP, Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983; 132: 6–13.CrossRefGoogle ScholarPubMed
38. Lacoste-Royal, G, Mathieu, M, Julien, J-P, et al. RFLP for Taql at the human neurofilament (NF-L) gene locus. Nucl Acids Res 1988; 16: 4184.CrossRefGoogle Scholar
39. Bech-Hansen, NT, Marshall, KJ, Kraus, SL. Human Taql RFLP recognized by neurofilament gene probes. Nucl Acids Res 1988; 16: 4183.CrossRefGoogle Scholar
40. Lacoste-Royal, G, Mathieu, M, Gauvreau, D. Hindi RFLP in the human gene for the heavy neurofilament subunit (NF-H). Nucl Acids Res 1989; 17: 6434.CrossRefGoogle Scholar
41. Botstein, D, White, RL, Skolnick, M, et al. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet 1980; 32: 314–331.Google ScholarPubMed
42. Kan, YW, Dozy, A. Polymorphism of DNA sequence adjacent to human ß-globin structural gene: relationship to sickle mutation. Proc Natl Acad Sci USA 1978; 75: 5631–5635.CrossRefGoogle Scholar
43. Humphries, SE, Talmud, PJ, Kessling, AM. Use of DNA polymorphisms of the apolipoprotein genes to study the role of genetic variation in the determination of serum lipid levels. In: Molecular Approaches to Human Polygenic Disease. Ciba Foundation Symposium 130. Chichester: John Wiley & Sons 1987: 128–149.Google Scholar
44. Langstrom, NS, Anderson, JP, Lindroos, HG, et al. Alzheimer’s disease-associated reduction of polysomal mRNA translation. Mol Brain Res 1989; 5: 259–269.CrossRefGoogle ScholarPubMed
45. Julien, J-P, Mushynski, WE. The distribution of phosphorylation sites among identified proteolytic fragments of mammalian neurofilaments. J Biol Chem 1983; 258: 4019–4025.CrossRefGoogle ScholarPubMed
46. Julien, J-P, Côté, F, Beaudet, L, et al. Sequence and structure of the mouse gene coding for the largest neurofilament subunit. Gene 1988; 68: 307–314.CrossRefGoogle ScholarPubMed
47. Hirokawa, N, Glicksman, MA, Willard, MB. Organization of mammalian neurofilament polypeptides within the neuronal cytoskeleton. J Cell Biol 1984; 98: 1523–1536.CrossRefGoogle ScholarPubMed