Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2011 Aug 12;28632:28456-65. doi: 10.1074/jbc.M111.226894.
Show Gene links
Show Anatomy links
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.
Salin-Cantegrel A
,
Rivière JB
,
Shekarabi M
,
Rasheed S
,
Dacal S
,
Laganière J
,
Gaudet R
,
Rochefort D
,
Lesca G
,
Gaspar C
,
Dion PA
,
Lapointe JY
,
Rouleau GA
.
???displayArticle.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.
Berger,
Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl- channel activity.
2005,
Pubmed
Dupré,
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum.
2003,
Pubmed
Egan,
Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects.
2004,
Pubmed
Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed
Harada,
Curcumin enhances cystic fibrosis transmembrane regulator expression by down-regulating calreticulin.
2007,
Pubmed
Howard,
The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.
2002,
Pubmed
,
Xenbase
Leduc-Nadeau,
Elaboration of a novel technique for purification of plasma membranes from Xenopus laevis oocytes.
2007,
Pubmed
,
Xenbase
Lipecka,
Rescue of DeltaF508-CFTR (cystic fibrosis transmembrane conductance regulator) by curcumin: involvement of the keratin 18 network.
2006,
Pubmed
Lu,
CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney.
2006,
Pubmed
,
Xenbase
Nezu,
A conserved hydrophobic tetrad near the C terminus of the secretory Na+-K+-2Cl- cotransporter (NKCC1) is required for its correct intracellular processing.
2009,
Pubmed
Salin-Cantegrel,
Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.
2007,
Pubmed
,
Xenbase
Salin-Cantegrel,
HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.
2008,
Pubmed
,
Xenbase
Shen,
KCl cotransport is an important modulator of human cervical cancer growth and invasion.
2003,
Pubmed
Simard,
Homooligomeric and heterooligomeric associations between K+-Cl- cotransporter isoforms and between K+-Cl- and Na+-K+-Cl- cotransporters.
2007,
Pubmed
,
Xenbase
Smit,
Missense mutation (G480C) in the CFTR gene associated with protein mislocalization but normal chloride channel activity.
1995,
Pubmed
,
Xenbase
Uyanik,
Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.
2006,
Pubmed
Xiong,
MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels.
2009,
Pubmed