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Scientists from NIH's National Human Genome Research Institute (NHGRI) and Undiagnosed Diseases Program (UDP) identified three children with the condition, two siblings and an unrelated child. The three children all had issues with motor coordination and speech, and one child had abnormalities in the cerebellum, the part of the brain involved in complex movement among other functions. Additionally, the children all had mutations in both copies of theATG4Dgene.
ATG4Daids in the cellular housekeeping process called autophagy, which cells use to break down and recycle damaged proteins and other defective pieces of the cell to stay healthy. Autophagy is a fundamental process used by cells throughout the body, but neurons are particularly dependent on autophagy for survival. However, little is known about howATG4Dcontributes to healthy neurons.
The first inclination ofATG4D's effects on brain health came from a 2015 study in which researchers identified a genetic neurological disease among Lagotto Romagnolo dogs, an Italian breed known for their fluffy coats and truffle-hunting abilities. The affected dogs had abnormal behavior, atrophy of the cerebellum, issues with motor coordination and eye movement andATG4Dmutations.
虽然这个2015年的研究精力充沛研究利益t inATG4D's role in the brain, scientists had yet to connectATG4Dto any neurological disease in humans.
"Among genetic diseases, we've solved many of the lower hanging fruits," said May Christine Malicdan, M.D., Ph.D., NHGRI staff scientist and senior author of the study. "Now, we're reaching for the higher fruits -- genes likeATG4Dthat are more difficult to analyze -- and we have the genomic and cellular tools to do so."
Computational analyses predicted that the three children'sATG4Dmutations would produce dysfunctional proteins. However, three other genes in the human genome serve very similar roles toATG4D,and in some cells, these other genes may compensate for a loss ofATG4D.
While all cells in the body share the same genome, some genes are more important for certain cells. When the researchers studied the children'sATG4Dmutations in skin cells, the variants did not affect the cells' recycling process, but this may not be true in the brain.
"The brain is so complex, and neurons have very specialized functions. To fit those functions, different neurons use different genes, so changes in redundant genes can have major impacts in the brain," said Malicdan.
To simulate cells that rely more heavily onATG4D, the researchers deleted the similar genes in cells grown in the laboratory and then inserted the children'sATG4Dmutations. The researchers determined the cells with the children'sATG4Dmutations could not carry out the necessary steps for autophagy, indicating that the children's symptoms are likely caused by insufficient cellular recycling.
Still, much aboutATG4Dremains unknown. "We have only a bird's eye view of many important cellular processes like autophagy," said Malicdan. A rare disease that involves changes in one gene can help tease apart how that gene acts in a broadly important cellular process.
Other components of autophagy are involved in common neurological disorders, such as Alzheimer's disease. Knowledge of this rare neurological disorder could lead to new avenues of research aboutATG4D's involvement in more common conditions.
"That's the million-dollar question in rare disease research," said Malicdan. "Rare diseases can help us understand biological pathways, so we can better understand how those pathways contribute to other rare and common conditions."
NIH researchers and clinicians continue to work with the children in this study, and the researchers are aiming to identify more patients. Treatments are many steps away, but by learning more aboutATG4Dand autophagy, researchers may be able to develop new treatments for this condition and others involving autophagy pathways.
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