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Title page for ETD etd-10112014-103334

Type of Document Dissertation
Author Ding, Jinlong
URN etd-10112014-103334
Title Role of KCC3 in the Hereditary Sensory Motor Neuropathy: HMSN/ACC
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Danny Winder Committee Chair
Anne Kenworthy Committee Member
Bruce Carter Committee Member
David Jacobson Committee Member
Eric Delpire Committee Member
  • Andermann Syndrome
  • SLC12A6
  • KCC3
Date of Defense 2014-08-21
Availability unrestricted
Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC or ACCPN) is an autosomal recessive disease caused by the disruption of the SLC12A6 gene, which encodes the K–Cl cotransporter-3 (KCC3). ACCPN is a rare neurodevelopmental and neurodegenerative disorder characterized by progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. A cloning mutation (E289G) of KCC3 was shown to render the cotransporter inactive in functional assays in Xenopus laevis oocytes. Through biochemical studies, the mutant E289G was shown to be glycosylation-deficient and failed to reach the plasma membrane. This result demonstrated that the glutamic acid residue (E289) was essential for proper trafficking and function of KCC3. Four tissue specific KCC3 knockout mouse lines were also created to explore the cell population origin of ACCPN. The loss of KCC3 in parvalbumin-positive neurons led to significant locomotor deficit, suggesting a crucial role of these neurons in the development of the locomotor deficit. Mice in which KCC3 deletion was driven by the neuron-specific enolase (NSE) did not develop any phenotype. Nociceptive neurons targeted with Nav1.8-driven CRE and Schwann cells targeted with a desert hedgehog-driven CRE were not involved in the development of ACCPN. These results establish that the parvalbumin-positive neuronal population is involved in the pathogenic development of ACCPN.
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