Skip to main content
SpringerLink
Log in

Mutation in the gene encoding lysosomal acid phosphatase (Acp2) causes cerebellum and skin malformation in mouse

  • Original Article
  • Published:
Neurogenetics Aims and scope Submit manuscript

Abstract.

We report a novel spontaneous mutation named nax in mice, which exhibit delayed hair appearance and ataxia in a homozygote state. Histological analyses of nax brain revealed an overall impairment of the cerebellar cortex. The classical cortical cytoarchitecture was disrupted, the inner granule cell layer was not obvious, the Purkinje cells were not aligned as a Purkinje cell layer, and Bergmann glias did not span the molecular layer. Furthermore, histological analyses of skin showed that the hair follicles were also abnormal. We mapped the nax locus between marker D2Mit158 and D2Mit100 within a region of 800 kb in the middle of chromosome 2 and identified a missense mutation (Gly244Glu) in Acp2, a lysosomal monoesterase. The Glu244 mutation does not affect the stability of the Acp2 transcript, however it renders the enzyme inactive. Ultrastructural analysis of nax cerebellum showed lysosomal storage bodies in nucleated cells, suggesting progressive degeneration as the underlying mechanism. Identification of Acp2 as the gene mutated in nax mice provides a valuable model system for studying the role of Acp2 in cerebellum and skin homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Eskelinen EL, Tanaka Y, Saftig P (2003) At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13:137–145

    Article  CAS  PubMed  Google Scholar 

  2. Gieselmann V (1995) Lysosomal storage diseases. Biochim Biophys Acta 1270:103–136

    CAS  PubMed  Google Scholar 

  3. Drexler HG, Gignac SM (1994) Characterization and expression of tartrate-resistant acid phosphatase (TRAP) in hematopoietic cells. Leukemia 8:359–368

    CAS  PubMed  Google Scholar 

  4. Gieselmann V, Hasilik A, Figura K von (1984) Tartrate-inhibitable acid phosphatase. Purification from placenta, characterization and subcellular distribution in fibroblasts. Hoppe Seyler Z Physiol Chem 365:651–660

    CAS  PubMed  Google Scholar 

  5. Clark SA, Ambrose WW, Anderson TR, Terrell RS, Toverud SU (1989) Ultrastructural localization of tartrate-resistant, purple acid phosphatase in rat osteoclasts by histochemistry and immunocytochemistry. J Bone Miner Res 4:399–405

    CAS  PubMed  Google Scholar 

  6. De Duve C (1959) Subcellular particles. In: Hayashi T (ed) Ronald Press, pp 128–159

  7. Geier C, Kreysing J, Boettcher H, Pohlmann R, Figura K von (1992) Localization of lysosomal acid phosphatase mRNA in mouse tissues. J Histochem Cytochem 40:1275–1282

    CAS  PubMed  Google Scholar 

  8. Hille A, Klumperman J, Geuze HJ, Peters C, Brodsky, FM, Figura K von (1992) Lysosomal acid phosphatase is internalized via clathrin-coated pits. Eur J Cell Biol 59:106–115

    CAS  PubMed  Google Scholar 

  9. Braun M, Waheed A, Figura K von (1989) Lysosomal acid phosphatase is transported to lysosomes via the cell surface. EMBO J 8:3633–3640

    CAS  PubMed  Google Scholar 

  10. Gottschalk S, Waheed A, Schmidt B, Laidler P, Figura K von, (1989) Sequential processing of lysosomal acid phosphatase by a cytoplasmic thiol proteinase and a lysosomal aspartyl proteinase. EMBO J 8:3215–3219

    CAS  PubMed  Google Scholar 

  11. Saftig P, Hartmann D, Lüllmann-Rauch R, Wolff J, Evers M, Köster A, Hetman M, Figura K von, Peters C (1997) Mice deficient in lysosomal acid phosphatase develop lysosomal storage in the kidney and central nervous system. J Biol Chem 272:18628–18634

    Article  CAS  PubMed  Google Scholar 

  12. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York

    Google Scholar 

  13. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  14. Waheed A, Van Etten RL, Gieselmann V, Figura K von (1985) Immunological characterization of human acid phosphatase gene products. Biochem Genet 23:309–319

    CAS  PubMed  Google Scholar 

  15. Rickmann M, Wolff JR (1995) S100 protein expression in subpopulations of neurons of rat brain. Neuroscience 67:977–991

    Article  CAS  PubMed  Google Scholar 

  16. Mannan AU, Nayernia K, Mueller C, Burfeind P, Adham IM, Engel W (2003) Male mice lacking the Theg (testicular haploid expressed gene) protein undergo normal spermatogenesis and are fertile. Biol Reprod 69:788–796

    CAS  PubMed  Google Scholar 

  17. Hatten ME, Heintz N (1995) Mechanisms of neural patterning and specification in the developing cerebellum. Annu Rev Neurosci 18:385–408

    CAS  PubMed  Google Scholar 

  18. Hatten ME (1990) Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain. Trends Neurosci 13:179–184

    Article  CAS  PubMed  Google Scholar 

  19. Paus R, Muller-Rover S, Van Der Veen C, Maurer M, Eichmuller S, Ling G, Hofmann U, Foitzik K, Mecklenburg L, Handjiski B (1999) A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. J Invest Dermatol 113:523–532

    Article  CAS  PubMed  Google Scholar 

  20. Jakob CG, Lewinski K, Kuciel R, Ostrowski W, Lebioda L (2000) Crystal structure of human prostatic acid phosphatase. Prostate 42:211–218

    Article  CAS  PubMed  Google Scholar 

  21. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna I, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A 93:11173–11178

    Article  CAS  PubMed  Google Scholar 

  22. Hess EJ (1996) Identification of the weaver mouse mutation: the end of the beginning. Neuron 16:1073–1076

    Article  CAS  PubMed  Google Scholar 

  23. Miyata T, Nakajima K, Mikoshiba K, Ogawa M (1997) Regulation of Purkinje cell alignment by reelin as revealed with CR-50 antibody. J Neurosci 17:3599–3609

    CAS  PubMed  Google Scholar 

  24. Goldowitz D, Cushing RC, Laywell E, D’Arcangelo G, Sheldon M, Sweet HO, Davisson M, Steindler D, Curran T, (1997) Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of reelin. J Neurosci 17:8767–8777

    CAS  PubMed  Google Scholar 

  25. Nakamura M, Sundberg JP, Paus R (2001) Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: annotated tables. Exp Dermatol 10:369–390

    Article  CAS  PubMed  Google Scholar 

  26. Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, Schmidt P, Schmahl W, Scherer J, Anton-Lamprecht I, Figura K von, Paus R, Peters C (2000) Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J 14:2075–2086

    Article  CAS  PubMed  Google Scholar 

  27. Suter A, Everts V, Boyde A, Jones SJ, Lullmann-Rauch R, Hartmann D, Hayman AR, Cox TM, Evans MJ, Meister T, Figura K von, Saftig P (2001) Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice. Development 128:4899–4910

    CAS  PubMed  Google Scholar 

  28. Fusek M, Vetvicka V (1994) Mitogenic function of human procathepsin D: the role of the propeptide. Biochem J 303:775–780

    CAS  PubMed  Google Scholar 

  29. Vetvicka V, Vetvickova J, Fusek M (1998) Effect of procathepsin D and its activation peptide on prostate cancer cells. Cancer Lett 129:55–59

    Article  CAS  PubMed  Google Scholar 

  30. Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83:481-489

    Article  CAS  PubMed  Google Scholar 

  31. Walkley SU (1998) Cellular pathology of lysosomal storage disorders. Brain Pathol 8:175–193

    CAS  PubMed  Google Scholar 

  32. Munoz R MV, Santos AC, Graziadio C, Pina-Neto JM (1997) Cerebello-trigeminal-dermal dysplasia (Gomez-Lopez-Hernandez syndrome): description of three new cases and review. Am J Med Genet 72:34–39

    Article  CAS  PubMed  Google Scholar 

  33. Keeler LC, Marsh SE, Leeflang EP, Woods CG, Sztriha L, Al-Gazali L, Gururaj A, Gleeson JG (2003) Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 73:656–662

    Article  CAS  PubMed  Google Scholar 

  34. Valente EM, Salpietro DC, Brancati F, Bertini E, Galluccio T, Tortorella G, Briuglia S, Dallapiccola B (2003) Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am J Hum Genet 73:663–670

    Article  CAS  PubMed  Google Scholar 

  35. Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM (1994) Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 8:280–284

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements.

This work was funded by the Deutsche Forschungsgemeinschaft through the DFG-Research Center for Molecular Physiology of the Brain to W.E. and M.R. The authors would like to thank S. Zimmermann for operational help, M. Wahl for assistance with structural biology programs, and K. von Figura for useful discussions and helping us with Acp2 enzymatic assay. A. Eberwein, M. Moeschner, and M. Steckel for technical assistance, and our animal housekeepers for breeding and maintaining these mice.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, University of Goettingen, Heinrich-Dueker-Weg 12, 37073, Goettingen, Germany

    Ashraf U. Mannan, Karim Nayernia & Wolfgang Engel

  2. Center of Anatomy, University of Goettingen, Kreuzbergring 36, 37075, Germany

    Elena Roussa, Micheal Rickmann, Joerg Maenner & Kerstin Krieglstein

  3. Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 , Erlangen, Germany

    Cornelia Kraus & André Reis

Authors
  1. Ashraf U. Mannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Roussa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cornelia Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Micheal Rickmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joerg Maenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karim Nayernia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kerstin Krieglstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. André Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wolfgang Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolfgang Engel.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mannan, A.U., Roussa, E., Kraus, C. et al. Mutation in the gene encoding lysosomal acid phosphatase (Acp2) causes cerebellum and skin malformation in mouse. Neurogenetics 5, 229–238 (2004). https://doi.org/10.1007/s10048-004-0197-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-004-0197-9

Keywords

Search

Navigation