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Israeli researchers have discovered important new information about the cause of a congenital central hypoventilation syndrome (CCHS), a rare, life-threatening neurological disorder characterized by inadequate breathing during sleep.

CCHS causes young children to stop breathing as soon as they fall asleep; if they fall asleep without ventilatory support, they may suffocate to death.

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Ben-Gurion University (BGU) of the Negev’s Prof. Gad Vatine and Tel Aviv University’s Dr. Avraham Ashkenazi were approached by the Yad Laneshima patient organization, urging them to work together to find treatments for the disorder.

Vatine is an expert in studying rare disorders using patient-specific stem cells, and Ashkenazi is an expert in tri-nucleotide repeat expansion disorders and protein clearance pathways. The two teamed up, initially under the sponsorship of Yad Laneshima and then the international CCHS Network, intrigued by the challenge.

That collaboration has yielded important new information about the cause of CCHS, which could lead to future treatments.

Their findings were published last month in the prestigious EMBO Journal.

CCHS is caused by a mutation in the PHOX2B gene, a key transcription factor in the development of the autonomic nervous system (ANS), a system that controls non-voluntary body functions such as breathing, digestion and heart rate. PHOX2B and eight other nuclear proteins that cause various neural disorders have a poly-alanine tract. In these disorders, the mutation expands the poly-alanine tract causes the disease.

PhD students Fatima Amer-Sarsour from Ashkenazi’s lab and Daniel Falik from Vatine’s lab identified a poly-alanine that is also present in one of the enzymes of the ubiquitin transfer system.

The teams led by Vatine and Ashkenazi discovered that the expansion mutation of the poly-alanine tract in PHOX2B (and in other poly-alanine disease-causing proteins) causes aberrant interaction with the poly-alanine recognizing enzyme of the ubiquitin transfer system. This interaction disrupts the proper ubiquitin transfer to neural proteins, which inhibits the ubiquitous normal functions, leading to cell death and eventually triggering CCHS.

To make this discovery clinically relevant, the Vatine lab at the Regenerative Medicine and Stem Cell (RMSC) research center at BGU used patient-specific stem cells, called induced pluripotent stem cells (iPSCs). They used a technique called ‘reprogramming’ that enables easily accessible cells (like blood cells or skin cells), to be “taken back in time” to become identical to embryonic stem cells (ESCs).

Unlike ESCs, iPSCs are generated without destroying embryos, and can be generated from any individual. The iPSCs from CCHS patients were then differentiated into PHOX2B-expressing cells of the ANS, which revealed the disease mechanism in the most vulnerable of the patient’s nerve cells.

“Now that we know what goes wrong in the CCHS patient neurons, we can start developing modalities to fix it with the goal of promoting neuron survival that will allow better quality of life for the patients,” the lead researchers said.

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Hana Levi Julian is a Middle East news analyst with a degree in Mass Communication and Journalism from Southern Connecticut State University. A past columnist with The Jewish Press and senior editor at Arutz 7, Ms. Julian has written for Babble.com, Chabad.org and other media outlets, in addition to her years working in broadcast journalism.