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Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1

Nature Genetics volume 27, pages 399405 (2001) | Download Citation

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Abstract

Neurofibromatosis type 1 (NF1) is a commonly inherited autosomal dominant disorder. Previous studies indicated that mice homozygous for a null mutation in Nf1 exhibit mid-gestation lethality, whereas heterozygous mice have an increased predisposition to tumors and learning impairments. Here we show that mice lacking the alternatively spliced exon 23a, which modifies the GTPase-activating protein (GAP) domain of Nf1, are viable and physically normal, and do not have an increased tumor predisposition, but show specific learning impairments. Our findings have implications for the development of a treatment for the learning disabilities associated with NF1 and indicate that the GAP domain of NF1 modulates learning and memory.

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Acknowledgements

We thank K. Thomas for the KT3NP4 neomycin cassette; R. White for support in the generation of the GAP4 antibody; D.H. Gutmann for help interpreting the immunohistochemistry; P.W. Frankland for discussions; and C.M. Spivak for inspiration and support. R.C.M. is supported by the GABBA Graduate Program (Oporto University) and the Portuguese Foundation for Science and Technology (BD 13854/97). This work was supported by a grant from the Department of Defense, U.S. Army Medical Research and Materiel Command (DAMD17-97-1-7339) to C.I.B.; grants from the NIH (R01 NS38480), the Neurofibromatosis Consortium and the Neurofibromatosis Foundation to A.J.S.; and a donation from C.M. Spivak to A.J.S.

Author information

Author notes

    • Tao Yang

    Present address: Brigham and Woman's Hospital, Boston, Massachusetts, USA.

    • Rui M. Costa
    •  & Tao Yang

    These authors contributed equally to this work.

Affiliations

  1. Departments of Neurobiology, Psychiatry and Psychology, BRI, UCLA, Los Angeles, California, USA.

    • Rui M. Costa
    •  & Alcino J. Silva
  2. Department of Molecular Genetics and Microbiology, Center for Mammalian Genetics, and the University of Florida Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA.

    • Tao Yang
    •  & Camilynn I. Brannan
  3. Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA.

    • Duong P. Huynh
    •  & Stefan M. Pulst
  4. Division of Medical Genetics, University of Utah, Salt Lake City, Utah, USA.

    • David H. Viskochil

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Correspondence to Alcino J. Silva or Camilynn I. Brannan.

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https://doi.org/10.1038/86898