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Protein plays broader role than originally thought in neurofibromatosis

JCI Journals

Neurofibromatosis type I is a common genetic disorder in which tumors grow along certain types of nerves and can also affect other tissues such as bone, heart, and skin. The condition is caused by a mutation in the gene coding for Neurofibromin (NF1), a GTPase-activating protein (GAP) that triggers the abnormal activation of the protein Ras, and clinical trials are currently underway using agents that downregulate Ras activity. However, it remains unclear whether modulation of Ras activity is the only, or even major function of neurofibromin.

In a study appearing online on August 10 in advance of print publication in the September issue of the Journal of Clinical Investigation, Fraz Ismat and colleagues from The Children's Hospital of Philadelphia examined a mouse model of Neurofibromatosis type I disease and showed that restoration of Ras-GAP activity through expression of the human NF1 GAP-related domain was able to restore normal cardiac development in these animals. However, not all pathologies associated with the loss of the neurofibromin protein were restored in these mice, indicating that neurofibromin is an important molecule in events beyond just Ras signaling. These results suggest that therapeutic approaches solely aimed at targeting Ras activity may not be sufficient to treat all tumors in patients with this disease.


TITLE: The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice


Fraz A. Ismat

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Phone: (267) 426-7937; Fax: (215) 590-5825; E-mail:

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