Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians
K. Roddier, BSc*,
T. Thomas, MD*,
G. Marleau, BSc,
A. M. Gagnon, BSc,
M. J. Dicaire, BSc,
A. St-Denis, MSc,
I. Gosselin, BSc,
A. M. Sarrazin, MD,
A. Larbrisseau, MD,
M. Lambert, MD,
M. Vanasse, MD,
D. Gaudet, MD, PhD,
G. A. Rouleau, MD, PhD and
B. Brais, MD, PhD
From the Laboratoire de neurogénétique (Drs. Thomas and Brais, K. Roddier, G. Marleau, A.M. Gagnon, M.J. Dicaire, A. St-Denis, and I. Gosselin), Centre de recherche du CHUM, Université de Montréal, Centre Hospitalier Régional de Lanaudière (Dr. Sarrazin), Saint-Charles-Borromée, Département de pédiatrie (Drs. Larbrisseau, Lambert, and Vanasse), Hôpital Sainte-Justine et Université de Montréal, Centre de médecine génique communautaire de l’Université de Montréal (Dr. Gaudet), Centre Hospitalier de la Saguamie, Saguenay, and McGill Health Centre (Dr. Rouleau), McGill University, Montréal, Québec, Canada.
Address correspondence and reprint requests to Dr. B. Brais, Centre de recherche du CHUM, Hôpital Notre-Dame-CHUM, M4211-L3, 1560, rue Sherbrooke est, Montréal, Québec, Canada H2L 4M1; e-mail: Bernard.Brais{at}umontreal.ca
Background: Hereditary sensory and autonomic neuropathy type2 (HSAN2; MIM 201300) is a rare recessive neuropathy typicallydiagnosed in the first decade. The 1973 study of a French Canadianfamily led to the definition of HSAN2.
Objectives: To demonstrate that the apparent higher prevalenceof HSAN2 in Quebec is due to the presence of two HSN2 mutationsand that carriers of different mutations appear to have a similarphenotype.
Methods: Through attending physicians, the authors recruitedFrench Canadian patients with HSAN2. Exclusion of linkage tothe known HSAN loci and linkage to the HSAN2 was performed usingstandard methods. Sequencing of the HSN2 gene was used to uncoverthe causal mutations.
Results: A large cluster of HSAN2 patients comprising 16 affectedindividuals belonging to 13 families was identified. The modeof inheritance is clearly autosomal recessive. All patientsoriginated from southern Quebec, and 75% are from the Lanaudièreregion. Whereas linkage to the HSAN1, 3, and 4 loci was excluded,linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencingof the HSN2 gene uncovered two French Canadian mutations anda novel nonsense mutation in a patient of Lebanese origin, allpredicted to lead to truncations of the HSN2 protein. The comparisonof clinical variables between patients with different genotypesdoes not suggest any difference in phenotype.
Conclusions: Two founder mutations are responsible for theapparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotypecorrelation does not suggest any significant clinical variability.
Additional material related to this article can be found onthe Neurology Web site. Go to www.neurology.org and scroll downthe Table of Contents for the May 24 issue to find the titlelink for this article.
*These authors have contributed equally to this work.
Supported by the ECOGENE-21 Interdisciplinary CIHR team grantof the Centre de médecine génique communautairede l’Université de Montréal, the Démogéniqueand Génétique communautaire axes of the Réseaude médecine génétique appliquée(RMGA) du Fonds de recherche en santé du Québec(FRSQ), and the Association de la Neuropathie sensorielle etautonomique héréditaire de type 2.
Dr. Brais is a chercheur-boursier of the FRSQ.
Received September 3, 2004. Accepted in final form January 25,2005.
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