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Founder Mutation for a-sarcoglycan-LGMD2D in a Magdalen Islands Acadian Cluster

Published online by Cambridge University Press:  18 February 2016

M. Tétreault ,
M. Srour ,
J. Allyson ,
I. Thiffault ,
L. Loisel ,
Y. Robitaille ,
JP. Bouchard  and
B. Brais
M. Tétreault*
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal Department of Molecular Neurogenetics, Montreal Neurological Institute, CHU-Sainte-Justine, Montreal
M. Srour
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal
J. Allyson
Affiliation:
Département de pathologie, CHU-Sainte-Justine, Montreal Département des sciences neurologiques, CHAUQ - Hôpital de l'Enfant-Jésus, Université Laval, Québec, QC, Canada
I. Thiffault
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal
L. Loisel
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal
Y. Robitaille
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal
JP. Bouchard
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal
B. Brais
Affiliation:
Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM, CHU-Sainte-Justine, Montreal
*
Laboratoire de neurogénétique, M4211-L3, Hôpital Notre-Dame-CHUM, 1560 Sherbrooke Est, Montreal, Quebec, H2L 4M1, Canada
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Abstract:

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Background:

We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence.

Methods:

Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region.

Results:

All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c.229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22.

Conclusion:

The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XlXth century, largely by Acadian immigrants.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 38 , Issue 5 , September 2011 , pp. 747 - 752
Copyright
Copyright © Canadian Neurological Sciences Federation 2011

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