Temporal manipulation of KCC3 expression in juvenile or adult mice suggests irreversible developmental deficit in hereditary motor sensory neuropathy with agenesis of the corpus callosum

Am J Physiol Cell Physiol. 2021 May 1;320(5):C722-C730. doi: 10.1152/ajpcell.00594.2020. Epub 2021 Feb 17.


Hereditary motor sensory neuropathy (HMSN/ACC) with agenesis of the corpus callosum (ACC) has been documented in the French-derived populations of Charlevoix and Saguenay/Lac St. Jean in Quebec, Canada, as well as a few sporadic families throughout the world. HMSN/ACC occurs because of loss-of-function mutations in the potassium-chloride cotransporter 3 (KCC3). In HMSN/ACC, motor deficits occur early in infancy with rapid and continual deterioration of motor and sensory fibers into juvenile and adulthood. Genetic work in mice has demonstrated that the disease is caused by loss of KCC3 function in neurons and particularly parvalbumin (PV)-expressing neurons. Currently, there are no treatments or cures for HMSN/ACC other than pain management. As genetic counseling in Quebec has increased as a preventative strategy, most individuals with HSMN/ACC are now adults. The onset of the disease is unknown. In particular, it is unknown if the disease starts early during development and whether it can be reversed by restoring KCC3 function. In this study, we used two separate mouse models that when combined to the PV-CreERT2 tamoxifen-inducible system allowed us to 1) disrupt KCC3 expression in adulthood or juvenile periods; and 2) reintroduce KCC3 expression in mice that first develop with a nonfunctional cotransporter. We show that disrupting or reintroducing KCC3 in the adult mouse has no effect on locomotor behavior, indicating that expression of KCC3 is critical during embryonic development and/or the perinatal period and that once the disease has started, reexpressing a functional cotransporter fails to change the course of HMSN/ACC.

Keywords: Andermann Syndrome; HSMN/ACC; KCC3 mouse model; parvalbumin-CreERT2; tamoxifen.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Agenesis of Corpus Callosum / genetics
  • Agenesis of Corpus Callosum / metabolism
  • Agenesis of Corpus Callosum / physiopathology
  • Agenesis of Corpus Callosum / therapy*
  • Animals
  • Behavior, Animal*
  • Disease Models, Animal
  • Female
  • Ganglia, Spinal / metabolism*
  • Ganglia, Spinal / physiopathology
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Genetic Therapy*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity*
  • Parvalbumins / metabolism
  • Peripheral Nervous System Diseases / genetics
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / physiopathology
  • Peripheral Nervous System Diseases / therapy*
  • Phenotype
  • Postural Balance
  • Rotarod Performance Test
  • Symporters / genetics
  • Symporters / metabolism*


  • Parvalbumins
  • Slc12a6 protein, mouse
  • Symporters

Supplementary concepts

  • Corpus callosum agenesis neuronopathy