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Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies

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Abstract

Neurofibromatosis type 1 (NF1) is the most common cancer predisposition syndrome affecting the nervous system, with elevated risk for both astrocytoma and peripheral nerve sheath tumors. NF1 is caused by a germline mutation in the NF1 gene, with tumors showing loss of the wild type copy of NF1. In addition, NF1 heterozygosity in surrounding stroma is important for tumor formation, suggesting an additional role of haploinsufficiency for NF1. Studies in mouse models and NF1 families have implicated modifier genes unlinked to NF1 in the severity of the disease and in susceptibility to astrocytoma and peripheral nerve sheath tumors. To determine if differences in Nf1 expression may contribute to the strain-specific effects on tumor predisposition, we examined the levels of Nf1 gene expression in mouse strains with differences in tumor susceptibility using quantitative polymerase chain reaction. The data presented in this paper demonstrate that strain background has as much effect on Nf1 expression levels as mutation of one Nf1 allele, indicating that studies of haploinsufficiency must be carefully interpreted with respect to strain background. Because expression levels do not correlate entirely with the susceptibility or resistance to tumors observed in the strain, these data suggest that either variation in Nf1 levels is not responsible for the differences in astrocytoma and peripheral nerve sheath tumor susceptibility in Nf1-/+;Trp53-/+cis mice, or that certain mouse strains have evolved compensatory mechanisms for differences in Nf1 expression.

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Acknowledgment

This research was supported by the Intramural Research Program of the NIH, NCI. J.J.H. was supported by a grant from the National Academies. Special thanks to R. Williams for donation of the recombinant inbred B×D38, B×D39, and B×D40 mouse strains. Special thanks to K. Fox for animal care assistance and K. Cichowski for helpful discussions. GeneNetwork and WebQTL are supported by grant NIH P20-MH 62009. The INIA dataset was generated with support from NIAAA-INIA to R. Williams. The HBP/Rosen Striatum dataset was generated with support from the NIH Human Brain Project (P20-DA 21131) to G. Rosen and R. Williams. All experiments were conducted in compliance with the current laws of the USA.

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Correspondence to Karlyne M. Reilly.

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Hawes, J.J., Tuskan, R.G. & Reilly, K.M. Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies. Neurogenetics 8, 121–130 (2007). https://doi.org/10.1007/s10048-006-0078-5

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  • DOI: https://doi.org/10.1007/s10048-006-0078-5

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