A mutation in the NF1 gene, which is known to trigger neurofibromin 1, control growth hormone secretion, according to a paper in Molecular Genetics.

The same mutation that causes neurofibromatosis type 1 also impairs growth hormone secretion, according to researchers at Washington University School of Medicine in St. Louis. The mutation in the NF1 gene affects brain levels of cyclic AMP (cAMP) and thus controls stature.

Prior research focused on neurofibromin’s effects on RAS protein, , which is linked to cell growth, proliferation and cancer. Normally, NF1 deactivates RAS proteins. In its absence, scientists believe that unchecked RAS can promote cancer development.

The researchers created a line of mice in which stem cells in the brain do not make the NF1 protein. They found that these mice were significantly smaller than normal and failed to grow and gain weight after birth.

They also noticed that the pituitary glands also were unusually small in these mice. The amount of a second hormone that triggers growth hormone release was also greatly reduced.

The question about the role of RAS protein activity still remained, however. “We wanted to know if we could blame this on RAS protein activity so we generated new mice with normal levels of neurofibromin expression but increased levels of RAS activation in brain stem cells,” says David H. Gutmann, M.D., Ph.D., a neurologist. “However, those mice were normal.”
NF1 also increases brain levels of cyclic AMP (cAMP), an important signaling molecule. Working with the same line of mice where stem cells in the brain do not make the NF1 protein, researchers fed pregnant mice and their newborns an agent that increased cAMP levels. The baby mice were closer to normal size, even though they still lacked neurofibromin in brain stem cells.

Dr. Gutmann suspects the mice didn’t completely return to normal because dietary supplementation of cAMP levels cannot match the natural ability of neurofibromin to control cAMP levels.

Dr. Gutmann has treatments in the works for neurofibromatosis 1 that restore the inhibitory effect neurofibromin normally has on RAS. The new results may mean treatments are also needed to restore neurofibromin’s effects on cAMP levels. “What we’ve learned also may help us gain insight into other disease processes,” Gutmann notes. “There are a number of other rare genetic abnormalities that cause short stature, and this same pathway may be involved.”

The results appear online in the journal Human Molecular Genetics.

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