NIH researchers find novel gene which may drive progression of a rare neuropathy in children

Neuropathy is a condition associated with a progressive decline in motor and sensory function; as such, patients can suffer from a wide range of symptoms, including muscle weakness and pain. National Institutes of Health (NIH) scientists now identify a genetic cause that might reveal itself as a potential drug target for a rare form of neuropathy.

The effort was a collaboration between NIH’s Institute of Neurological Disorders and Stroke, Vanderbilt University and the Yale School of Medicine. They published their findings in the journal Science Signaling.

The study exploited whole exome sequencing to identify any causal mutations in a 10-year-old child with early onset, progressive neuropathy. One of the hits to come back from the analysis was a gain-of-function mutation in a gene called KCC3. This gene usually codes for a protein that negatively regulates neuronal swelling, but the mutation causes the protein to instead become overactive, resulting in neuronal shrinkage.

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Mutations of KCC3 had been observed in neuropathy previously, but this was the first study to identify a gain-of-function mutation in this gene.

Interestingly, patients with a loss-of-function KCC3 mutation have progressive motor and sensory function decline, with clear behavioral and developmental symptoms. In contrast, the gain-of-function mutation only affected motor function and was absent of the other symptoms.

The scientists are recapitulating the disease in a mouse model to widen the mechanism of how this type of KCC3 mutation causes this rare form of neuropathy.

“We wanted to take a closer look at the direct effects of this mutation on the muscles and nerves, so we created a mouse model with the same genetic change as our patient,” said the senior author of the study, Carsten Bonnemann, in an NIH news release. “When we tested this mouse, we saw many of the same physical deficits, including problems with movement and coordination, and a decrease in the ability of neurons to send signals to the muscles. This shows that this mutation is likely to be the main cause for our patient’s neuropathy.”

The exact mechanism remains unclear, but the teams plan to target KCC3 with a known inhibitor--and diuretic to treat fluid retention, kidney disorders and high blood pressure--furosemide, in a mouse model with the same mutation. Furosemide is believed to inhibit KCC3 to an even greater extent in the setting of the gain-of-function mutation.

“We were able to identify what this particular mutation does, so we have a specific target for therapeutic development. Because furosemide inhibits the function of the transporter that is improperly activated in our patient, we may one day be able to use drugs like furosemide to intervene in the progression of neuropathies caused by this type of mutation,” added Bonnemann.

- see the release
- here’s the article abstract

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