title: A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration.
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 (Lyst(Ing3618)) 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 Lyst(Ing3618) 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 Lyst(Ing3618 )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.
authors.affiliation: Division of Neuropathology, Institute of Pathology, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.forename: Andreas
authors.initials: A
authors.lastname: Osanger
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kohlmann
authors.forename: Martin
authors.initials: M
authors.lastname: Augustin
authors.forename: Guido
authors.initials: G
authors.lastname: Piontek
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heinzmann
authors.forename: Gisela
authors.initials: G
authors.lastname: Jennen
authors.forename: Andreas
authors.initials: A
authors.lastname: Russ
authors.forename: Kaspar
authors.initials: K
authors.lastname: Matiasek
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stumm
authors.forename: Juergen
authors.initials: J
authors.lastname: Schlegel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064026:Calbindins; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics*; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010503:Periodic Acid-Schiff Reaction; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D064026:Calbindins; D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; D008840:Microfilament Proteins; D011506:Proteins; D064030:S100 Calcium Binding Protein G; D033921:Vesicular Transport Proteins; D004247:DNA