YKT6 gene variants may cause new genetic disorders: study Health


A recent joint investigation identified unusual mutations in the YKT6 gene as the source of a new neurological disease, including developmental delay, severe progressive liver disease, and increased risk of liver cancer.

Abnormal mutations in the YKT6 gene are the source of a novel neurological disease. (Representative file photo)

The study, published in Genetics in Medicine, was led by Dr. Hugo Belen, Distinguished Service Professor at Baylor College of Medicine and Dr. Wendy Chung, principal investigator and head of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital. Pediatrics at Boston Children's Hospital.

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“It is known that the YKT6 gene plays an important role in many intracellular vesicular trafficking events in cells, but this is the first time it has been linked to a genetically inherited disorder,” said Dr. Belen. “This study, using patient samples and fruit flies, provides a solid experimental foundation for future studies to better understand this new disease and develop treatments.”

YKT6 gene variants disrupt brain development and, sometimes, liver function

In collaboration with Dr. Mythili Ganapathy at Columbia University Irving Medical Center, Dr. Paula Hertel and Davut Pahlavan at Texas Children's Hospital, and Dr. James Lupsky at Baylor College of Medicine, and using the GeneMatcher tool and the Baylor Genetics Clinical Diagnostics Laboratory, the researchers And this team of physicians found three unrelated individuals with the wrong meaning (corresponding to the wrong spelling). One word) differs in both copies of the YKT6 gene.

All three individuals had early disease onset (at four to six months of age) as well as failure to thrive. Two of them had a similar missense variant that caused the tyrosine amino acid at position 185 to be changed to cysteine ​​(Tyr185Cys). On the other hand, the third child had a variant that caused the same amino acid change but in a different location (Tyr64Cys) of the YKT6 protein. Interestingly, in addition to developmental delays and neurological defects in all three children, only two individuals with the Tyr185Cys variant had liver dysfunction and a possible increased risk of developing liver cancer.

“Interestingly, both individuals with the Tyr185Cys variant belong to Syrian/St. Thomas Christians from Kerala, India, a group that currently comprises about 5 million people worldwide,” said Dr. Maithili Ganapathy. “Our genetic lineage analysis suggests that this variant likely arose from a common ancestor before the community split.”

YKT6 gene variants impair autophagy

To assess how YKT6 variants result in the observed disease pathology, the Belen team studied a fruit fly version of this gene that is most similar to its human counterpart.

“We found that the fly version of this protein is expressed in the fat body and brain that correspond to the human liver and central nervous system, respectively,” said Dr. Mengqi Ma, one of the first authors and a postdoctoral fellow in the Belen lab. , Said. “In addition, fly strains with loss of function mutations in this gene were lethal.”

Furthermore, they observed that Ykt6 mutant flies expressing the normal fly version of the Ykt6 gene had longer average lifespans. However, transgenic flies expressing different forms of the disease were less effective in restoring lifespan and other symptoms. While the lifespan and locomotion of Ykt6 mutant flies expressing Tyr65Cys (equivalent to human Tyr64Cys) were normal, the lifespan and locomotion defects of flies expressing Tyr186Cys (equivalent to human Tyr185Cys) were severely reduced. “Our results showed that fly Ykt6 Tyr186Cys causes more severe defects than Tyr65Cys,” said Dr. Ma, “suggesting that the related human YKT6 Tyr185Cys is a more severe variant than Tyr64Cys.”

To understand why these variants behave differently, he delved deeper into their biology.

YKT6 belongs to the SNARE family of proteins that regulate the flow of protein traffic to various compartments within the cell. In mammalian cells, YKT6 mediates the fusion of two cellular organelles – the autophagosome and the lysosome – to form the autolysosome, within which 'used' cellular proteins, lipids and other molecules are degraded and recycled back for future use. goes. This process, called autophagy, is important for the proper function and health of cells.

The team found that deletion of fly Ykt6 led to abnormal accumulation of proteins involved in autophagosome formation and the autophagic cargo receptor, indicating disruption of the autophagy pathway. Further studies showed that, like lethality and other defects, the fly Tyr186Cys (equivalent to human Tyr185Cys) was less efficient in correcting symptoms than a normal copy of the Ykt6 gene. Furthermore, they observed that while the initiation of autophagy was normal, steps involved in the breakdown of cellular waste were impaired in the absence of Ykt6.

Dr. Maithili Ganapathy said, “Based on our findings, we recommend the YKT6 gene as a candidate for carrier screening in the Syrian/St. Thomas Christian community of Kerala.”

“Our work suggests that children with YKT6 liver disease will also need to be screened for hepatocellular carcinoma,” said Dr. Paula Hertel.

“In summary, we have discovered YKT6 variants as the cause of a new developmental disorder affecting brain function and, in some cases, also liver function, which provides us with valuable insight into a new genetic disease. However Additional studies with more patients will be needed to accurately understand the pathogenesis and identify potential therapeutic targets for this condition, Dr. Belen said.

This story is published from a wire agency feed without any modifications to the text. Only the headline has been changed.

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