Hostname: page-component-848d4c4894-2xdlg Total loading time: 0 Render date: 2024-06-30T04:09:27.808Z Has data issue: false hasContentIssue false
  • English
  • Français

SPG4 Founder Effect in French Canadians with Hereditary Spastic Paraplegia

Published online by Cambridge University Press:  02 December 2014

Inge A. Meijer ,
Nicolas Dupré ,
Bernard Brais ,
Patrick Cossette ,
Judith St-Onge ,
Marie-France Rioux ,
Melanie Benard  and
Guy A. Rouleau
Inge A. Meijer
Affiliation:
Center for the Study of Brain Diseases, CHUM Research Center, Notre-Dame Hospital
Nicolas Dupré
Affiliation:
Center for the Study of Brain Diseases, CHUM Research Center, Notre-Dame Hospital
Bernard Brais
Affiliation:
Center for the Study of Brain Diseases, CHUM Research Center, Notre-Dame Hospital
Patrick Cossette
Affiliation:
Center for the Study of Brain Diseases, CHUM Research Center, Notre-Dame Hospital
Marie-France Rioux
Affiliation:
Service de neurologic, Centre hospitalier de l'Université de Sherbrooke, Sherbrooke, QC, Canada
Melanie Benard
Affiliation:
Center for the Study of Brain Diseases, CHUM Research Center, Notre-Dame Hospital
Guy A. Rouleau
Affiliation:
Center for the Study of Brain Diseases, CHUM Research Center, Notre-Dame Hospital
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.
Background:

The most common cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) is mutations in the SPG4 gene. We have previously identified novel SPG4 mutations in a collection of North American families including the c.G1801A mutation present in two families from Quebec. The aim of this study is to estimate the frequency of the c.G1801A mutation in the French Canadian (FC) population and to determine whether this mutation originates from a common ancestor.

Methods:

We collected and sequenced exon 15 in probands of 37 families. Genotypes of markers flanking the SPG4 gene were used to construct haplotypes in five families. Clinical information was reviewed by a neurologist with expertise in HSP.

Results:

We have identified three additional unrelated families with the c.G1801A mutation and haplotype analysis revealed that all five families share a common ancestor. The mutation is present in 7% of all our FC families and explains half of our spastin linked FC families. The phenotype associated with the c.G1801A genotype is pure HSP with bladder involvement.

Conclusion:

In this study we have determined that the relative frequency of the c.G1801A mutation in our FC collection is 7%, and approximately 50% in the spastin positive FC group. This mutation is the most common HSP mutation identified in this population to date and is suggestive of a founder effect in Quebec.

Résumé:

RÉSUMÉ:Contexte:

La cause la plus fréquente de la paraplégie spastique héréditaire (PSH) dominante autosomique est une mutation du gène SPG4. Nous avons déjà identifié de nouvelles mutations du gène SPG4 dans un groupe de familles nord-américaines, dont la mutation c.G1801A qui est présente chez 2 familles du Québec. Le but de cette étude était d'estimer la fréquence de la mutation c.G1801A dans la population canadienne-française (CF) et de déterminer si cette mutation provient d'un ancêtre commun.

Méthodes :

Nous avons recueilli et séquencé l'exon 15 de chacun des cas index des 37 familles. Le génotypage de marqueurs adjacents au gène SPG4 a été utilisé pour construire des haplotypes dans 5 familles. Les données cliniques ont été révisées par un neurologue ayant une expertise dans le domaine de la PSH.

Résultats :

Nous avons identifié 3 autres familles non apparentées qui ont la mutation c.G1801A et l'analyse des haplotypes a montré que ces 5 familles ont un ancêtre commun. La mutation est présente chez 7% de nos familles CF et explique la maladie liée à la spastine chez la moitié de nos familles CF. Le phénotype associé au génotype cG1801A est une PSH pure avec atteinte vésicale.

Conclusion:

Nous avons établi que la fréquence relative de la mutation cG1801A chez nos cas CF est de 7% et de 50% dans le groupe de cas CF positifs pour la spastine. C'est la mutation la plus fréquente dans le gène de la PSH qui ait été identifiée dans cette population jusqu'à maintenant et nos données sont compatibles avec la présence d'un effet fondateur au Québec.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 34 , Issue 2 , May 2007 , pp. 211 - 214
Copyright
Copyright © The Canadian Journal of Neurological 2007

References

1. Harding, AE. Hereditary spastic paraplegias. [Review]. Semin Neurol. 1993; 13:333–6.Google Scholar
2. Reid, E. Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet. 2003; 40:81–6.Google Scholar
3. Fink, JK. Advances in the hereditary spastic paraplegias. Exp Neurol. 2003; 184 Suppl 1:S106–10.Google Scholar
4. Simpson, MA, Cross, H, Proukakis, C, Pryde, A, Hershberger, R, Chatonnet, A, et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet. 2003; 73:1147–56.CrossRefGoogle ScholarPubMed
5. Hodgkinson, CA, Bohlega, S, Abu-Amero, SN, Cupler, E, Kambouris, M, Meyer, BF, et al. A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology. 2002; 59:1905–9.Google Scholar
6. Klebe, S, Azzedine, H, Durr, A, Bastien, P, Bouslam, N, Elleuch, N, et al. Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain. 2006; Jun 129(Pt 6): 1456–6.Google Scholar
7. Zuchner, S, Kail, ME, Nance, MA, Gaskell, PC, Svenson, IK, Marchuk, DA, et al. A new locus for dominant hereditary spastic paraplegia maps to chromosome 2p12. Neurogenetics. 2006; 7:127–9.Google Scholar
8. Crosby, AH, Proukakis, C. Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet. 2002; 71:1009–16.Google Scholar
9. Rainier, S, Chai, JH, Tokarz, D, Nicholls, RD, Fink, JK. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet. 2003; 73:967–71.Google Scholar
10. Durr, A, Davoine, CS, Paternotte, C, von Fellenberg, J, Cogilinicean, S, Coutinho, P et al. Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2. Brain. 1996; 119 (Pt 5): 1487–96.Google Scholar
11. Soderblom, C, Blackstone, C. Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther. 2006; 109:42–56.CrossRefGoogle ScholarPubMed
12. Depienne, C, Tallaksen, C, Lephay, JY, Bricka, B, Poea-Guyon, S, Fontaine, B, et al. Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases. J Med Genet. 2006; 43:259–65.CrossRefGoogle ScholarPubMed
13. Errico, A, Ballabio, A, Rugarli, E. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002; 15:153–63.Google Scholar
14. Roll-Mecak, A, Vale, RD. The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules. Curr Biol. 2005; 15:650–5.Google Scholar
15. Hazan, J, Fonknechten, N, Mavel, D, Paternotte, C, Samson, D, Artiguenave, F, et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. 1999; 23:296–303.CrossRefGoogle ScholarPubMed
16. Hentati, A, Deng, HX, Zhai, H, Chen, W, Yang, Y, Hung, WY et al. Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. Neurology. 2000; 55:1388–90.CrossRefGoogle ScholarPubMed
17. Burger, J, Fonknechten, N, Hoeltzenbein, M, Neumann, L, Bratanoff, E, Hazan, J, et al. Hereditary spastic paraplegia caused by mutations in the SPG4 gene. Eur J Hum Genet. 2000; 8:771–6.CrossRefGoogle ScholarPubMed
18. Fonknechten, N, Mavel, D, Byrne, P, Davoine, CS, Cruaud, C, Bonsch, D, et al. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet. 2000; 9:637–44.Google Scholar
19. Yip, AG, Durr, A, Marchuk, DA, Ashley-Koch, A, Hentati, A, Rubinsztein, DC, et al. Meta-analysis of age at onset in spastin-associated hereditary spastic paraplegia provides no evidence for a correlation with mutational class. J Med Genet. 2003; 40:e106.Google Scholar
20. Meijer, I, Hand, C, Cossette, P, Figlewicz, D, Rouleau, G. Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Arch Neurol. 2002; 59:281–6.Google Scholar
21. Meijer, IA, Cossette, P, Roussel, J, Benard, M, Toupin, S, Rouleau, GA. A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1. Ann Neurol. 2004; 56:579–82.CrossRefGoogle Scholar
22. McDermott, CJ, Burness, CE, Kirby, J, Cox, LE, Rao, DG, Hewamadduma, C, et al. Clinical features of hereditary spastic paraplegia due to spastin mutation. Neurology. 2006; 67:45–51.Google Scholar
23. Crippa, F, Panzeri, C, Martinuzzi, A, Arnoldi, A, Redaelli, F, Tonelli, A, et al. Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Arch Neurol. 2006; 63:750–5.CrossRefGoogle Scholar
24. Sauter, S, Miterski, B, Klimpe, S, Bonsch, D, Schols, L, Visbeck, A, et al. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat. 2002; 20:127–32.Google Scholar
25. Depienne, C, Fedirko, E, Forlani, S, Cazeneuve, C, Ribai, P, Feki, I, et al. Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. J Med Genet. 2006; 43:259–65.Google Scholar
26. Laberge, AM, Michaud, J, Richter, A, Lemyre, E, Lambert, M, Brais, B, et al. Population history and its impact on medical genetics in Quebec. Clin Genet. 2005; 68:287–301.Google Scholar
27. Dupre, N, Bouchard, J-P, Brais, B, Rouleau, GA. Hereditary ataxia, spastic paraparesis and neuropathy in the French-Canadian population. Can J Neurol Sci. 2006; 33:149–57.CrossRefGoogle ScholarPubMed
28. Kibar, Z, Dube, MP, Powell, J, McCuaig, C, Hayflick, SJ, Zonana, J, et al. Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping. Eur J Hum Genet. 2000; 8:372–80.CrossRefGoogle ScholarPubMed
29. Orlacchio, A, Kawarai, T, Totaro, A, Errico, A, St George-Hyslop, PH, Rugarli, EI, et al. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol. 2004; 61:849–55.Google Scholar
30. Namekawa, M, Nelson, I, Ribai, P, Durr, A, Denis, E, Stevanin, G, et al. A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene. Neurogenetics. 2006; 7:131–2.Google Scholar
31. Nielsen, JE, Johnsen, B, Koefoed, P, Scheuer, KH, Gronbech-Jensen, M, Law, I, et al. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. Eur J Neurol. 2004; 11:817–24.Google Scholar
32. Meyer, T, Schwan, A, Dullinger, JS, Brocke, J, Hoffmann, KT, Nolte, CH, et al. Early-onset ALS with long-term survival associated with spastin gene mutation. Neurology. 2005; 65:141–3.Google Scholar
33. Alber, B, Pernauer, M, Schwan, A, Rothmund, G, Hoffmann, KT, Brummer, D, et al. Spastin related hereditary spastic paraplegia with dysplastic corpus callosum. J Neurol Sci. 2005; 236:9–12.Google Scholar
34. Nielsen, JE, Koefoed, P, Kjaergaard, S, Jensen, LN, Norremolle, A, Hasholt, L. Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection. Prenat Diagn. 2004; 24:363–6.CrossRefGoogle ScholarPubMed
35. Orso, G, Martinuzzi, A, Rossetto, MG, Sartori, E, Feany, M, Daga, A. Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. J Clin Invest. 2005; 115:3026–34.CrossRefGoogle Scholar