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Diversity of ARSACS Mutations in French-Canadians

Published online by Cambridge University Press:  23 September 2014

I. Thiffault ,
M.J. Dicaire ,
M. Tetreault ,
K.N. Huang ,
J. Demers-Lamarche ,
G. Bernard ,
A. Duquette ,
R. Larivière ,
K. Gehring  and
A. Montpetit
...Show all authors
I. Thiffault
Affiliation:
Neurogenetics of Motion Laboratory, Montreal
M.J. Dicaire
Affiliation:
Neurogenetics of Motion Laboratory, Montreal Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
M. Tetreault
Affiliation:
Neurogenetics of Motion Laboratory, Montreal
K.N. Huang
Affiliation:
Neurogenetics of Motion Laboratory, Montreal
J. Demers-Lamarche
Affiliation:
Neurogenetics of Motion Laboratory, Montreal
G. Bernard
Affiliation:
Neurogenetics of Motion Laboratory, Montreal
A. Duquette
Affiliation:
Neurogenetics of Motion Laboratory, Montreal
R. Larivière
Affiliation:
Neurogenetics of Motion Laboratory, Montreal Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
K. Gehring
Affiliation:
Neuromuscular Group, Department of Biochemistry, Montreal Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
A. Montpetit
Affiliation:
Genome Quebec Innovation Centre, Montreal
P.S. McPherson
Affiliation:
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
A. Richter
Affiliation:
CHU Sainte-Justine, Université de Montréal, Montréal
L. Montermini
Affiliation:
CHU Sainte-Justine, Université de Montréal, Montréal
J. Mercier
Affiliation:
CHU Sainte-Justine, Université de Montréal, Montréal Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
G.A. Mitchell
Affiliation:
CHU Sainte-Justine, Université de Montréal, Montréal
N. Dupré
Affiliation:
Département des sciences neurologiques, CHUQ – Hôpital de l'Enfant-Jésus, Université Laval, Québec
C. Prévost
Affiliation:
Clinique des Maladies Neuromusculaires, CSSS de Jonquière, Saguenay
J.P. Bouchard
Affiliation:
Département des sciences neurologiques, CHUQ – Hôpital de l'Enfant-Jésus, Université Laval, Québec Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
J. Mathieu
Affiliation:
Clinique des Maladies Neuromusculaires, CSSS de Jonquière, Saguenay
B. Brais*
Affiliation:
Neurogenetics of Motion Laboratory, Montreal Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University CHU Sainte-Justine, Université de Montréal, Montréal Clinique des Maladies Neuromusculaires, CSSS de Jonquière, Saguenay Fondation de l'Ataxie de Charlevoix-Saguenay-CIHR Emerging Team on rare diseases
*
Neurogenetics of Motion Laboratory, Neuromuscular Group, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada Email: [email protected]
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Abstract:

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Background:

The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability.

Methods:

Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin.

Results:

A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin.

Conclusions:

The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 40 , Issue 1 , January 2013 , pp. 61 - 66
Copyright
Copyright © The Canadian Journal of Neurological 2013

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