Giant axon formation in mice lacking Kell, XK, or Kell and XK: animal models of McLeod neuroacanthocytosis syndrome

Am J Pathol. 2014 Mar;184(3):800-7. doi: 10.1016/j.ajpath.2013.11.013. Epub 2014 Jan 7.

Abstract

McLeod neuroacanthocytosis syndrome (MLS) is a rare X-linked multisystem disease caused by XK gene mutations and characterized by hematological and neurological abnormalities. XK, a putative membrane transporter, is expressed ubiquitously and is covalently linked to Kell, an endothelin-3-converting enzyme (ECE-3). Absence of XK results in reduction of Kell at sites where both proteins are coexpressed. To elucidate the functional roles of XK, Kell, and the XK-Kell complex associated with pathogenesis in MLS, we studied the pathology of the spinal cord, anterior roots, sciatic nerve, and skeletal muscle from knockout mouse models, using Kel(-/-), Xk(-/-), Kel(-/-)Xk(-/-), and wild-type mice aged 6 to 18 months. A striking finding was that giant axons were frequently associated with paranodal demyelination. The pathology suggests probable anterograde progression from the spinal cord to the sciatic nerve. The neuropathological abnormalities were found in all three genotypes, but were more marked in the double-knockout Kel(-/-)Xk(-/-) mice than in either Kel(-/-) or Xk(-/-) mice. Skeletal muscles from Xk(-/-) and Kel(-/-)Xk(-/-) mice showed mild abnormalities, but those from Kel(-/-) mice were similar to the wild type. The more marked neuropathological abnormalities in Kel(-/-)Xk(-/-) mice suggest a possible functional association between XK and Kell in nonerythroid tissues.

Publication types

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

MeSH terms

  • Amino Acid Transport Systems, Neutral / genetics
  • Amino Acid Transport Systems, Neutral / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Axons / metabolism
  • Axons / pathology*
  • Disease Models, Animal
  • Endothelin-Converting Enzymes
  • Female
  • Genotype
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Neuroacanthocytosis / genetics
  • Neuroacanthocytosis / pathology*

Substances

  • Amino Acid Transport Systems, Neutral
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Xkh protein, mouse
  • Aspartic Acid Endopeptidases
  • KEL protein, human
  • Metalloendopeptidases
  • Endothelin-Converting Enzymes

Supplementary concepts

  • Neuroacanthocytosis, Mcleod Type