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


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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Figure 1: Strategy and analysis of targeted disruptions of Nf1 exon 23a.
Figure 2: Spatial learning in the water maze.
Figure 3: Contextual discrimination.
Figure 4: Motor performance in the rota-rod.
Figure 5: Social transmission of food preferences.


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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.

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

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Costa, R., Yang, T., Huynh, D. et al. Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet 27, 399–405 (2001).

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