Distal truncation of KCC3 in non–French Canadian HMSN/ACC families

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Distal truncation of KCC3 in non–French Canadian HMSN/ACC families

A. Salin-Cantegrel, MSc, J. -B. Rivière, MSc, N. Dupré, MD, MSc, F.

M. Charron, MSc, M. Shekarabi, PhD, L. Karéméra, C. Gaspar, PhD, J.

Horst, MD, M. Tekin, MD, G. Deda, MD, A. Krause, MD, PhD, M. M.

Lippert, MD, M. A.A.P. Willemsen, MD, R. Jarrar, MD, J. -Y.

Lapointe, PhD and G. A. Rouleau, MD, PhD

From the Centre for the Study of Brain Diseases (A.S.-C., J.-B.R.,

M.S., L.K., C.G., G.A.R.), CHUM Research Centre–Notre-Dame Hospital

and the University of Montreal, Québec; Department of Neurological

Sciences (N.D.), CHAUQ-Enfant-Jesus, Quebec City; Department of

Physics (F.M.C., J.-Y.L.), Université de Montreal, Québec, Canada;

Institut fur Humangenetik (J.H.), Universitatsklinikum Munster,

Germany; Pediatric Molecular Genetics Department (M.T., G.D.),

Ankara University, School of Medicine, Turkey; Department of Human

Genetics (A.K., M.M.L.), National Health Laboratory Service and

University of Witwatersand, South Africa; Department of Paediatric

Neurology (M.A.A.P.W.), University Medical Centre, St. Radboud,

Nijmegen, The Netherlands; and Gillette Children's Specialty Health

Care (R.J.), St. , MN.

Background: Hereditary motor and sensory neuropathy with agenesis of

the corpus callosum (HMSN/ACC) is a severe and progressive autosomal

recessive polyneuropathy. Mutations in the potassium-chloride

cotransporter 3 gene (KCC3) were identified as responsible for

HMSN/ACC in the French Canadian (FC) population. In the present

study, the authors were interested in finding new mutations in non-

FC populations, assessing the activity of mutant proteins and

refining genotype-phenotype correlations.

Methods: The authors screened KCC3 for mutations using direct

sequencing in six non-FC HMSN/ACC families. They then assessed the

functionality of the most common mutant protein using a flux assay

in Xenopus laevis oocytes.

Results: The authors identified mutations in exon 22 of KCC3: a

novel mutation (del + 2994-3003; E1015X) in one family, as well as a

known mutation (3031CT; R1011X) found in five unrelated families and

associated with two different haplotypes. The function of the

cotransporter was abolished, although a limited amount of mutant

proteins were correctly localized at the membrane.

Conclusions: KCC3 mutations in exon 22 constitute a recurrent

mutation site for hereditary motor and sensory neuropathy with

agenesis of the corpus callosum (HMSN/ACC), regardless of ethnic

origin, and are the most common cause of HMSN/ACC in the non–French

Canadian (FC) families analyzed so far. Therefore, for genetic

analysis, exon 22 screening should be prioritized in non-FC

populations. Finally, the R1011X mutation leads to the abrogation of

KCC3's function in Xenopus laevis oocytes, likely due to impaired

transit of the cotransporter.