Study: New insights into the role of the MLL4 gene in Kabuki syndrome

BUFFALO, NY – Scientists have known for years that mutations in the MLL4 gene can cause Kabuki syndrome, a rare developmental disorder.

But a study published on January 11 in Nature Communications It shines new details of how this happened. (Photos are available by contacting Charlotte Hsu at UB Media Relations at [email protected])

The research suggests that MLL4 controls the production of neurons that secrete growth hormone-releasing hormone (GHRH) in a part of the brain called the hypothalamus. Mice without working copies of the MLL4 gene in this region had stunted growth and significantly fewer GHRH neurons. Mice with only one copy of the gene had similar problems.

These are important insights, because GHRH stimulates growth hormone production in the pituitary gland in both mice and humans. While the effects of Kabuki syndrome vary, delayed growth and short stature are common among patients.

“Looking at our findings, it is assumed that MLL4 inactivation leads to a loss of GHRH neurons, leading to the typical growth deficiency in Kabuki patients,” says Jay Lee, Ph.D, professor of biological sciences at the University of Buffalo College of Arts and Sciences. “We have also investigated the epigenetic activity of MLL4, and our studies indicate that MLL4 could be a major non-genomic target molecule for treating the various symptoms of Kabuki syndrome.”

“This is the first study that demonstrates the role of MLL4 in determining the fate of neuron types during evolution, a major advance in our efforts to understand how cell fates are determined through epigenetics, and an important question that remains to be answered in modern neuroscience,” says Seunghee. Lee, assistant professor of pharmacy at Seoul National University.

Jae Lee and Seunghee Lee are two senior authors of the study. The first author is Christian Huisman, Ph.D., postdoctoral scientist at the University of Oregon Health and Science.

A detailed look at MLL4 business

For patients, parents and caregivers, new knowledge about the biology of rare diseases provides hope and lays a basis for developing treatments, says Jay Lee, who is the father of a child with a different rare genetic disorder (FOXG1 syndrome).

Although mutations in different genes can lead to Kabuki syndrome, mutations in MLL4 are one of the most common causes of the disorder.

As part of the new study, the team used cutting-edge techniques to investigate the molecular mechanisms by which MLL4 controls GHRH neurogenesis in embryonic development in mice. The research shows that MLL4 helps activate various genes involved in the production of GHRH neurons, and found that the transcription factor called NRF1 is a key partner in this process.

Moreover, scientists have shown that small chemicals that mimic the epigenetic actions of MLL4 can help restore GHRH neuron production.

While growth hormone therapies are already in place, Jay Lee says the new research creates opportunities to explore treatment pathways for other symptoms of Kabuki syndrome.

“Kabuki syndrome has many other symptoms that cannot be treated, and targeting epigenetic activities of MLL4 could be a feasible strategy for treating other symptoms,” says Jay Lee. The principle we found – dealing with the epigenetic roles of MLL4 in cell type specification – may apply. On different symptoms. “


In addition to Jae Lee, Seunghee Lee, and Huisman, study authors include Young A Kim at Seoul University; Shin Jeon, Bongjin Shin, Young Yong Park, Midha KC and Su Kyung Lee at UB Jeonghoon Choi from Oregon Health and Science University; And Su Jeong Lim, Sung Min Youn and Sangsoo Kim at Soongsil University.

The research was funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases, both of which are part of the US National Institutes of Health. Soongsil University Research Fund; Korea National Research Foundation; And the Korea Institute for Health Industry Development.

http: // www.Buffalo.Edo /News /release /2021 /01 /003.programming language
http: // dx.Resonate.Deer /10.1038 /s41467-020-20511-7

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