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: Adèle Salin-Cantegrel, Jean-Baptiste Rivière, Masoud Shekarabi, Sarah Rasheed, Sandra Dacal, Janet Laganière, Rébecca Gaudet, Daniel Rochefort, Gaëtan Lesca, Claudia Gaspar, Patrick A Dion, Jean-Yves Lapointe, Guy A Rouleau
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 32 Pg. 28456-65 (Aug 12 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21628467 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• SLC12A6 protein, human
• Symporters

Topics

• Agenesis of Corpus Callosum (genetics, metabolism)
• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• HeLa Cells
• Hereditary Sensory and Motor Neuropathy (genetics, metabolism)
• Humans
• Mutation, Missense
• Nerve Tissue Proteins (genetics, metabolism)
• Protein Transport
• Sequence Deletion
• Symporters (genetics, metabolism)
• Xenopus laevis