Acta Neuropathologica

, Volume 112, Issue 3, pp 267–276

A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration

  • Martina Rudelius
  • Andreas Osanger
  • Stephanie Kohlmann
  • Martin Augustin
  • Guido Piontek
  • Ulrich Heinzmann
  • Gisela Jennen
  • Andreas Russ
  • Kaspar Matiasek
  • Gabriele Stumm
  • Juergen Schlegel
Original Paper

DOI: 10.1007/s00401-006-0092-6

Cite this article as:
Rudelius, M., Osanger, A., Kohlmann, S. et al. Acta Neuropathol (2006) 112: 267. doi:10.1007/s00401-006-0092-6

Abstract

Disturbance of intracellular trafficking plays a major role in several neurodegenerative disorders including Alzheimer or Parkinson’s disease. The Chediak–Higashi syndrome (CHS), a life-threatening autosomal recessive disease with frequent mutations in the LYST gene, and its animal model, the beige mouse, are both characterized by lysosomal defects with accumulation of giant lysosomes. Clinically they manifest as hypopigmentation, abnormal bleeding and increased susceptibility to infection with various degrees of involvement of the nervous system. In the course of a recessive N-ethyl-N-nitrosurea (ENU) mutagenesis screen, we identified the first murine missense mutation in the lysosomal trafficking regulator gene (LystIng3618) located at a highly conserved position in the WD40 protein domain. Nearly all described human Lyst alleles lead to protein truncation and fatal childhood CHS. Only four different missense mutations have been reported in patients with adolescent or adult forms of CHS involving the nervous system. Interestingly, the LystIng3618 model presents with a predominant neurodegenerative phenotype with progressive degeneration and loss of Purkinje cells and lacks severe impairment of the immune system. Therefore, the LystIng3618 allele could represent a new model for adult CHS with neurological impairment. It could also provide an important tool to elucidate the role of neuronal lysosomal trafficking in the pathophysiology of neurodegeneration.

Keywords

Neurodegeneration Purkinje cell degeneration Lysosomal storage disorder Chediak–Higashi syndrome Beige Lyst 

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Martina Rudelius
    • 1
  • Andreas Osanger
    • 2
  • Stephanie Kohlmann
    • 2
  • Martin Augustin
    • 2
  • Guido Piontek
    • 1
  • Ulrich Heinzmann
    • 1
  • Gisela Jennen
    • 1
  • Andreas Russ
    • 2
  • Kaspar Matiasek
    • 3
  • Gabriele Stumm
    • 2
  • Juergen Schlegel
    • 1
  1. 1.Division of Neuropathology, Institute of PathologyTechnical University of MunichMuenchenGermany
  2. 2.Ingenium Pharmaceuticals AGMunichGermany
  3. 3.Institute of PathologyLudwig Maximilians UniversityMunichGermany

Personalised recommendations