The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.

  • Wilson W
  • Kennaugh J
  • Kugler J
 et al. 
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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.

Author-supplied keywords

  • *Agenesis of Corpus Callosum
  • *Heredodegenerative Disorders
  • 129 Strain
  • 3 et 4 du
  • Agenesis of Corpus Callosum
  • Agenesis of Corpus Callosum: genetics
  • Agenesis of Corpus Callosum: metabolism
  • Agenesis of Corpus Callosum: pathology
  • Andermann Syndrome
  • Animal
  • Animals
  • Biopsy
  • Blotting
  • Brain
  • Brain: pathology
  • Canada
  • Cerebral/ph [Physiology]
  • Child
  • Chromosome Aberrations
  • Chromosomes
  • Cisterna Magna/pa [Pathology]
  • Conduction
  • Consanguinity
  • Corpus Callosum
  • Corpus Callosum/pa [Pathology]
  • Corpus Callosum: embryology
  • DNA
  • Deafness
  • Deafness: genetics
  • Deafness: metabolism
  • Disease Models
  • Dominance
  • EEG
  • Electromyography
  • Exons
  • Female
  • Fluorescence
  • Gene Deletion
  • Genes
  • Genetic
  • Haplotypes
  • Hereditary Sensory and Motor Neuropathy
  • Hereditary Sensory and Motor Neuropathy: genetics
  • Hereditary Sensory and Motor Neuropathy: metabolis
  • Hereditary Sensory and Motor Neuropathy: pathology
  • Heredodegenerative Disorders
  • Homozygote
  • Human
  • Humans
  • Hypertension
  • Hypertension: genetics
  • Hypertension: metabolism
  • Immunoblotting
  • Inbred C57BL
  • Knockout
  • Magnetic Resonance Imaging
  • Male
  • Member 1
  • Mice
  • Microscopy
  • Models
  • Molecular Sequence Data
  • Mutation
  • Mutation: genetics
  • Nervous System
  • Nervous System/di [
  • Nervous System/ge [G
  • Nervous System: gene
  • Nervous System: meta
  • Nervous System: path
  • Neurologic Examination
  • Neurons
  • Neurons: metabolism
  • Neurons: pathology
  • Neuropathy
  • Open Reading Frames
  • Pair 15
  • Pedigree
  • Peripheral Nervous System Diseases
  • Peripheral Nervous System Diseases: genetics
  • Phenotype
  • Polymorphism
  • Potassium chloride cotransport
  • Preschool
  • Protein Engineering
  • Protein Engineering: methods
  • Recessive
  • Recombination
  • Reverse Transcriptase Polymerase Chain Reaction
  • SLC12A6
  • Sequence Analysis
  • Sodium-Potassium-Chloride Symporters
  • Sodium-Potassium-Chloride Symporters: genetics
  • Sodium-Potassium-Chloride Symporters: physiology
  • Solute Carrier Family 12
  • Southern
  • Spinal Cord
  • Spinal Cord: pathology
  • Sural Nerve/pa [Pathology]
  • Symporters
  • Symporters: biosynthesis
  • Symporters: deficiency
  • Symporters: genetics
  • Symporters: physiology
  • Time Factors
  • Transgenic
  • Turkey
  • Xenopus
  • acc
  • cell volume
  • cell volumes and ions
  • cerebral edema
  • cl
  • cl cotransport
  • co-transporteur k
  • corpus callosum
  • dent les isoformes 1
  • des mutations au sein
  • erythrocytes
  • hereditary motor and sensory
  • hmsn
  • k
  • k transport modes
  • kcc
  • kcc2
  • kcc3
  • kcc3 isoform mu-
  • n ethylmaleimide
  • neuropathy with agenesis of
  • nkcc1
  • osmotic fragility
  • osr1
  • tants
  • wnk-spak

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Authors

  • W G Wilson

  • J M Kennaugh

  • J P Kugler

  • J F Reynolds

  • G. Uyanik

  • N. Elcioglu

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