Japanese researchers have discovered the genetic defect that causes a form of dwarfism, which may allow development of a treatment. The results of the new study will be presented Wednesday, June 18, at The Endocrine Society’s 90th Annual Meeting in San Francisco.

“Although growth hormone is the main regulator of body height, all the causes of low height are not clear yet,” said coauthor Kazushige Sakaguchi, MD, PhD, professor and chairman of the molecular cell biology department at Wakayama Medical University in Japan. “We still do not know the exact biological mechanisms of a significant percentage of the patients with dwarfism.”

Using mice with the defective gene, Sakaguchi and his co-workers found that one subset of growth hormone-insensitive dwarfism is caused by a defect in the signal, or cellular message, to increase body height. This defective signaling occurs “downstream” of the growth hormone receptor, he said. A receptor is the molecular “hand” that holds onto another molecule. With this dwarfism, the growth hormone receptor is intact, unlike the genetic defect in Laron syndrome, a form of dwarfism in which those affected lack this receptor needed for growth.

Instead, after growth hormone binds to the intact receptor, another receptor called EphA4 binds to the growth hormone receptor and augments the signal for growth hormone, the authors found. The signal is reduced when EphA4 is defective. As a result, there are low circulating levels of insulin-like growth factor 1, a protein that plays an important role in childhood growth, the study showed. In the mice, it accounted for short stature.

As a gene vector, the researchers injected a retrovirus containing EphA4 into connective tissue cells from the mice, which rescued expression of EphA4. After stimulation with growth hormone, the cells expressing EphA4 showed an enhanced growth hormone signal, Sakaguchi said.

“These findings suggest that the EphA4-mediated signal is one of the modifying molecules that affect the growth hormone signal,” he said.

Previously, scientists knew only that EphA4 is required for guidance of nerve cells, he said. EphA4 is stimulated by ephrin-A, a molecule expressed on the cell surface of many tissues.

Based on their study results, Sakaguchi said, “It may be possible to invent a hormone therapy for dwarfism that works through EphA4.”

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