X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron

J Pathol. 2015 Jun;236(2):241-50. doi: 10.1002/path.4511. Epub 2015 Mar 3.


ATP7A is a copper-transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron.

Keywords: ATP7A; Menkes disease; X-linked spinal muscular atrophy; copper; motor neuron; motor neuropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / deficiency*
  • Adenosine Triphosphatases / genetics
  • Animals
  • Cation Transport Proteins / deficiency*
  • Cation Transport Proteins / genetics
  • Copper / metabolism
  • Copper-Transporting ATPases
  • Gene Deletion
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / pathology
  • Genetic Diseases, X-Linked / physiopathology
  • Lameness, Animal / genetics
  • Lameness, Animal / physiopathology
  • Mice, Inbred C57BL
  • Motor Neuron Disease / genetics
  • Motor Neuron Disease / pathology
  • Motor Neuron Disease / physiopathology
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Motor Neurons / physiology
  • Muscle, Skeletal / innervation
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / pathology
  • Muscular Atrophy, Spinal / physiopathology
  • Mutation, Missense / genetics
  • Spinal Cord / chemistry


  • Atp7a protein, mouse
  • Cation Transport Proteins
  • Copper
  • Adenosine Triphosphatases
  • Copper-Transporting ATPases

Supplementary concepts

  • Spinal Muscular Atrophy, Distal, X-Linked 3