Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J (original) (raw)

Nature volume 448, pages 68–72 (2007)Cite this article

Abstract

Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells1. Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome–lysosome axis in yeast2. Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the ‘pale tremor’ mouse. Positional cloning identified insertion of ETn2β (early transposon 2β)3 into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC (suppressor of actin) domain PtdIns(3,5)P2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome–lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot–Marie–Tooth disorder is designated CMT4J.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006)
    Article ADS CAS Google Scholar
  2. Michell, R. H., Heath, V. L., Lemmon, M. A. & Dove, S. K. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63 (2006)
    Article CAS Google Scholar
  3. Maksakova, I. A. et al. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2, e2 (2006)
    Article Google Scholar
  4. Hughes, W. E., Cooke, F. T. & Parker, P. J. Sac phosphatase domain proteins. Biochem. J. 350, 337–352 (2000)
    Article CAS Google Scholar
  5. Duex, J. E., Tang, F. & Weisman, L. S. The Vac14p–Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover. J. Cell Biol. 172, 693–704 (2006)
    Article CAS Google Scholar
  6. Rudge, S. A., Anderson, D. M. & Emr, S. D. Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14–Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Mol. Biol. Cell 15, 24–36 (2004)
    Article CAS Google Scholar
  7. Duex, J. E., Nau, J. J., Kauffman, E. J. & Weisman, L. S. Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels. Eukaryot. Cell 5, 723–731 (2006)
    Article CAS Google Scholar
  8. Bonangelino, C. J. et al. Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p. J. Cell Biol. 156, 1015–1028 (2002)
    Article CAS Google Scholar
  9. Gary, J. D. et al. Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member. Mol. Biol. Cell 13, 1238–1251 (2002)
    Article CAS Google Scholar
  10. Rutherford, A. C. et al. The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport. J. Cell Sci. 119, 3944–3957 (2006)
    Article CAS Google Scholar
  11. Marks, M. S. & Seabra, M. C. The melanosome: membrane dynamics in black and white. Nature Rev. Mol. Cell Biol. 2, 738–748 (2001)
    Article CAS Google Scholar
  12. Schroder, J. M. Neuropathology of Charcot–Marie–Tooth and related disorders. Neuromolecular Med. 8, 23–42 (2006)
    Article Google Scholar
  13. Szigeti, K., Garcia, C. A. & Lupski, J. R. Charcot–Marie–Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet. Med. 8, 86–92 (2006)
    Article Google Scholar
  14. Begley, M. J. et al. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc. Natl Acad. Sci. USA 103, 927–932 (2006)
    Article ADS CAS Google Scholar
  15. Bolino, A. et al. Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. J. Cell Biol. 167, 711–721 (2004)
    Article CAS Google Scholar
  16. Bolino, A. et al. Charcot–Marie–Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nature Genet. 25, 17–19 (2000)
    Article CAS Google Scholar
  17. Bonneick, S. et al. An animal model for Charcot–Marie–Tooth disease type 4B1. Hum. Mol. Genet. 14, 3685–3695 (2005)
    Article CAS Google Scholar
  18. Senderek, J. et al. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot–Marie–Tooth neuropathy type 4B2/11p15. Hum. Mol. Genet. 12, 349–356 (2003)
    Article CAS Google Scholar
  19. Stendel, C. et al. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4. Am. J. Hum. Genet. (in the press); preprint at http://www.journals.uchicago.edu/AJHG/journal/preprints/AJHG44688.preprint.pdf (2007)
  20. Verhoeven, K. et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot–Marie–Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727 (2003)
    Article CAS Google Scholar
  21. Zuchner, S. et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot–Marie–Tooth disease. Nature Genet. 37, 289–294 (2005)
    Article Google Scholar
  22. Schmitt-John, T. et al. Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nature Genet. 37, 1213–1215 (2005)
    Article CAS Google Scholar
  23. Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817–830 (2006)
    Article CAS Google Scholar
  24. Adamska, M., Billi, A. C., Cheek, S. & Meisler, M. H. Genetic interaction between Wnt7a and Lrp6 during patterning of dorsal and posterior structures of the mouse limb. Dev. Dyn. 233, 368–372 (2005)
    Article Google Scholar
  25. Escayg, A. et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 24, 343–345 (2000)
    Article CAS Google Scholar
  26. Rainier, S., Sher, C., Reish, O., Thomas, D. & Fink, J. K. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch. Neurol. 63, 445–447 (2006)
    Article Google Scholar
  27. Li, J. et al. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J. Comp. Neurol. 498, 252–265 (2006)
    Article CAS Google Scholar
  28. Kohrman, D. C., Harris, J. B. & Meisler, M. H. Mutation detection in the med and med J alleles of the sodium channel Scn8a. Unusual splicing due to a minor class AT–AC intron. J. Biol. Chem. 271, 17576–17581 (1996)
    Article CAS Google Scholar

Download references

Acknowledgements

For discussions and advice we are grateful to A. Dlugosz, E. Feldman, D. Goldowitz, J. Hammond, L. Isom, J. M. Jones, A. Lieberman, M. Khajavi, J. Swanson, K. Verhey and S. H. Yang. S. Cheek and M. Hancock provided technical assistance. This research was supported by NIH research grants (M.H.M., L.W. and J.R.L.) and NIH predoctoral training (C.Y.C.).

Author information

Authors and Affiliations

  1. Department of Human Genetics,,
    Clement Y. Chow, Maja Adamska & Miriam H. Meisler
  2. Life Sciences Institute,,
    Yanling Zhang, Natsuko Jin & Lois S. Weisman
  3. Department of Cellular and Developmental Biology, and,
    Lois S. Weisman
  4. Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA,
    James J. Dowling
  5. Departments of Molecular and Human Genetics,,
    Kensuke Shiga, Kinga Szigeti & James R. Lupski
  6. Pediatrics, and,,
    James R. Lupski
  7. Neurology, Baylor College of Medicine,
    Kinga Szigeti
  8. Texas Children’s Hospital, Houston, Texas 77030, USA,
    James R. Lupski
  9. Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA,
    Michael E. Shy, Jun Li & Xuebao Zhang
  10. John D. Dingle VA Medical Center, Detroit, Michigan 48201, USA,
    Jun Li

Authors

  1. Clement Y. Chow
    You can also search for this author inPubMed Google Scholar
  2. Yanling Zhang
    You can also search for this author inPubMed Google Scholar
  3. James J. Dowling
    You can also search for this author inPubMed Google Scholar
  4. Natsuko Jin
    You can also search for this author inPubMed Google Scholar
  5. Maja Adamska
    You can also search for this author inPubMed Google Scholar
  6. Kensuke Shiga
    You can also search for this author inPubMed Google Scholar
  7. Kinga Szigeti
    You can also search for this author inPubMed Google Scholar
  8. Michael E. Shy
    You can also search for this author inPubMed Google Scholar
  9. Jun Li
    You can also search for this author inPubMed Google Scholar
  10. Xuebao Zhang
    You can also search for this author inPubMed Google Scholar
  11. James R. Lupski
    You can also search for this author inPubMed Google Scholar
  12. Lois S. Weisman
    You can also search for this author inPubMed Google Scholar
  13. Miriam H. Meisler
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toMiriam H. Meisler.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information 1

This file contains Supplementary Video Legend, Supplementary Figures 1-10 with Legends and Supplementary Discussion. (PDF 4003 kb)

Supplementary Information 2

This file contains Supplementary Video 1 which shows the typical movement disorder of the plt mouse. The mouse is four weeks old. (MOV 2031 kb)

Rights and permissions

About this article

Cite this article

Chow, C., Zhang, Y., Dowling, J. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.Nature 448, 68–72 (2007). https://doi.org/10.1038/nature05876

Download citation

This article is cited by

Editorial Summary

Pale tremor gene discovery

The appearance of a spontaneous mutation in mice in a University of Michigan research laboratory has led to the identification of the gene responsible for a form of the inherited neurodegenerative disease called Charcot–Marie–Tooth disorder. The pale tremor mice, which develop a multi-organ neurodegeneration, are mutated in a homologue of the yeast gene Fig4, which is required to maintain normal levels of the signalling lipid PtdIns(3,5)P2. Prior to this work, there had been no indication that the low abundance signalling compound PtdIns(3,5)P2 had a specific role in neuronal maintenance.