Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.
BACKGROUND
Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2.


OBJECTIVE
To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype.


METHODS
Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations.


RESULTS
A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudière region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype.


CONCLUSIONS
Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.
Roddier
K
K
Laboratoire de neurogénétique, Centre de recherche du CHUM, Université de Montréal, Montréal, Québec, Canada.
Thomas
T
T
Marleau
G
G
Gagnon
A M
AM
Dicaire
M J
MJ
St-Denis
A
A
Gosselin
I
I
Sarrazin
A M
AM
Larbrisseau
A
A
Lambert
M
M
Vanasse
M
M
Gaudet
D
D
Rouleau
G A
GA
Brais
B
B
D000328:Adult; D000368:Aged; D001483:Base Sequence / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases; D011792:Quebec / Q000453:epidemiology; D000076204:WNK Lysine-Deficient Protein Kinase 1
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human