title: Transit defect of potassium-chloride Co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum.
abstract: Missense and protein-truncating mutations of the human potassium-chloride co-transporter 3 gene (KCC3) cause hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), which is a severe neurodegenerative disease characterized by axonal dysfunction and neurodevelopmental defects. We previously reported that KCC3-truncating mutations disrupt brain-type creatine kinase-dependent activation of the co-transporter through the loss of its last 140 amino acids. Here, we report a novel and more distal HMSN/ACC-truncating mutation (3402C → T; R1134X) that eliminates only the last 17 residues of the protein. This small truncation disrupts the interaction with brain-type creatine kinase in mammalian cells but also affects plasma membrane localization of the mutant transporter. Although it is not truncated, the previously reported HMSN/ACC-causing 619C → T (R207C) missense mutation also leads to KCC3 loss of function in Xenopus oocyte flux assay. Immunodetection in Xenopus oocytes and in mammalian cultured cells revealed a decreased amount of R207C at the plasma membrane, with significant retention of the mutant proteins in the endoplasmic reticulum. In mammalian cells, curcumin partially corrected these mutant protein mislocalizations, with more protein reaching the plasma membrane. These findings suggest that mis-trafficking of mutant protein is an important pathophysiological feature of HMSN/ACC causative KCC3 mutations.
authors.affiliation: Centre of Excellence in Neuromics, University of Montreal, Centre Hospitalier de l'Université de Montréal-Research Center, Montreal, Quebec H2L 4M1, Canada.
authors.forename: Adèle
authors.initials: A
authors.lastname: Salin-Cantegrel
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.forename: Masoud
authors.initials: M
authors.lastname: Shekarabi
authors.forename: Sarah
authors.initials: S
authors.lastname: Rasheed
authors.forename: Sandra
authors.initials: S
authors.lastname: Dacal
authors.forename: Janet
authors.initials: J
authors.lastname: Laganière
authors.forename: Rébecca
authors.initials: R
authors.lastname: Gaudet
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Lesca
authors.forename: Claudia
authors.initials: C
authors.lastname: Gaspar
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Lapointe
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D006367:HeLa Cells; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D017384:Sequence Deletion; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000096922:K Cl- Cotransporters
chemical_list: D009419:Nerve Tissue Proteins; D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters