Missense mutation in mouse GALC mimics human gene defect and offers new insights into krabbe disease

Gregory Potter, Marta Santos, Muriel T. Davisson, David H. Rowitch, Daniel Marks, Ernesto R. Bongarzone, Magdalena Petryniak

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease.GALCtwi-5J homozygotesshow loss of enzymatic activity despite normal levels of precursor protein, and manifest amore severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, theCNSdoes not manifest significant demyelination. In contrast, thePNSis severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.

Original languageEnglish (US)
Article numberddt190
Pages (from-to)3397-3414
Number of pages18
JournalHuman Molecular Genetics
Volume22
Issue number17
DOIs
StatePublished - Sep 2013

Fingerprint

Galactosylceramidase
Globoid Cell Leukodystrophy
Psychosine
Missense Mutation
Gliosis
Genes
Mutation
Protein Precursors
Nonsense Codon
Demyelinating Diseases
Myelin Sheath
Nervous System
Axons
Half-Life
Disease Progression
Pediatrics
Phenotype
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Potter, G., Santos, M., Davisson, M. T., Rowitch, D. H., Marks, D., Bongarzone, E. R., & Petryniak, M. (2013). Missense mutation in mouse GALC mimics human gene defect and offers new insights into krabbe disease. Human Molecular Genetics, 22(17), 3397-3414. [ddt190]. https://doi.org/10.1093/hmg/ddt190

Missense mutation in mouse GALC mimics human gene defect and offers new insights into krabbe disease. / Potter, Gregory; Santos, Marta; Davisson, Muriel T.; Rowitch, David H.; Marks, Daniel; Bongarzone, Ernesto R.; Petryniak, Magdalena.

In: Human Molecular Genetics, Vol. 22, No. 17, ddt190, 09.2013, p. 3397-3414.

Research output: Contribution to journalArticle

Potter, G, Santos, M, Davisson, MT, Rowitch, DH, Marks, D, Bongarzone, ER & Petryniak, M 2013, 'Missense mutation in mouse GALC mimics human gene defect and offers new insights into krabbe disease', Human Molecular Genetics, vol. 22, no. 17, ddt190, pp. 3397-3414. https://doi.org/10.1093/hmg/ddt190
Potter, Gregory ; Santos, Marta ; Davisson, Muriel T. ; Rowitch, David H. ; Marks, Daniel ; Bongarzone, Ernesto R. ; Petryniak, Magdalena. / Missense mutation in mouse GALC mimics human gene defect and offers new insights into krabbe disease. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 17. pp. 3397-3414.
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