title: Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.
abstract: 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 (3031C-->T; 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.
authors: Centre for the Study of Brain Diseases, CHUM Research Centre-Notre-Dame Hospital and the University of Montreal, Montreal, Québec, Canada.
authors: A
authors: A
authors: Salin-Cantegrel
authors: J-B
authors: JB
authors: Rivière
authors: N
authors: N
authors: Dupré
authors: F M
authors: FM
authors: Charron
authors: M
authors: M
authors: Shekarabi
authors: L
authors: L
authors: Karéméra
authors: C
authors: C
authors: Gaspar
authors: J
authors: J
authors: Horst
authors: M
authors: M
authors: Tekin
authors: G
authors: G
authors: Deda
authors: A
authors: A
authors: Krause
authors: M M
authors: MM
authors: Lippert
authors: M A A P
authors: MA
authors: Willemsen
authors: R
authors: R
authors: Jarrar
authors: J-Y
authors: JY
authors: Lapointe
authors: G A
authors: GA
authors: Rouleau
mesh_terms: D061085:Agenesis of Corpus Callosum; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009154:Mutation / Q000235:genetics*; D009421:Nervous System Malformations / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D009865:Oocytes; D010375:Pedigree; D011792:Quebec; D027981:Symporters / Q000737:chemistry / Q000235:genetics*; D044465:White People; D014982:Xenopus laevis; D000096922:K Cl- Cotransporters
chemical_list: D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters