April 13, 2024

Rare variants in the YKT6 gene cause new neurological disorder, study finds

A recent collaborative study discovered rare variants in YKT6 gene as the cause of a new neurological disorder characterized by developmental delays along with severe progressive liver disease and a potential risk of liver cancer. The study, published in Genetics in MedicineHugo Bellen, Distinguished Service Professor at Baylor College of Medicine and principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and Dr. Pediatrics at Boston Children’s Hospital.

“It is known that YKT6 The gene plays important roles 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. Bellen. “This study, using samples from patients and fruit flies, provides a solid experimental basis for future studies to better understand this new disease and develop therapies.”

YKT6 gene variants disrupt brain development and sometimes liver function

In collaboration with Dr. Mythily Ganapathi of Columbia University Irving Medical Center, Drs. Paula Hertel and Davut Pehlivan of Texas Children’s Hospital, and Dr. James Lupski of Baylor College of Medicine, and using the GeneMatcher tool and diagnostic laboratory Baylor Genetics clinician, this team of researchers and doctors found three unrelated individuals with missense (analogous to misspellings in a word) variants in both copies of YKT6 gene.

All three individuals had early onset of the disease (four to six months of age) with delayed growth. Two of them had an identical missense variant, due to which the amino acid tyrosine at position 185 was changed to cysteine ​​(Tyr185Cys). On the other hand, the third child carried a variant that caused the same amino acid change, but in a different location (Tyr64Cys) of the YKT6 protein. Interestingly, in addition to the developmental delays and neurological defects observed in all three children, only the two individuals with the Tyr185Cys variant had liver dysfunction and a potential risk of developing liver cancer.

Interestingly, both individuals with the Tyr185Cys variant belong to the Syrian/St. Thomas Christians of Kerala, India, a group currently estimated to number about 5 million individuals worldwide. Our genetic lineage analysis suggests that this variant likely originated from a common ancestor before the community split.”

Mythily Ganapathi of Columbia University Irving Medical Center

YKT6 gene variants impair autophagy

To evaluate how YKT6 variants result in the observed disease pathologies, Bellen’s team studied the fruit fly version of this gene, which is quite similar to its human counterpart.

“We found that the fly version of this protein is expressed in the fat body and brain, which are analogous to the human liver and central nervous system, respectively,” said Dr. Mengqi Ma, one of the first authors and postdoctoral fellow in the lab. Bellen. , he said. “Furthermore, 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 Ykt6 the genetic flies had an average lifespan. However, transgenic flies expressing fly versions of the disease variants were less effective in restoring life expectancy and other symptoms. While Ykt6 mutant flies expressing Tyr65Cys (same as human Tyr64Cys) had normal lifespan and locomotion, those expressing Tyr186Cys (same as human Tyr185Cys) had severely reduced lifespan and locomotor defects. “Our results showed that the fly Ykt6 Tyr186Cys causes more severe defects than Tyr65Cys,” added Dr. Ma, “suggesting that the corresponding human YKT6 Tyr185Cys is a more severe variant than Tyr64Cys.”

To understand why these variants behaved differently, they delved deeper into their biology.

YKT6 belongs to the SNARE family of proteins that regulate the flow of protein trafficking to various compartments within the cell. In mammalian cells, YKT6 mediates the fusion of two cellular organelles – autophagosomes and lysosomes to form autolysosomes – within which cellular proteins, lipids and other “used” molecules are degraded and recycled back for future use. This process called autophagy is fundamental for the proper functioning and health of cells.

The team found that fly loss Ykt6 led to an abnormal accumulation of proteins involved in the formation of the autophagosome and the autophagic cargo receptor, indicating a block in the autophagy pathway. Other studies revealed that, like lethality and other defects, the fly Tyr186Cys (same as human Tyr185Cys) was less efficient at reversing symptoms compared to a normal copy of the virus. Ykt6 gene. Furthermore, they observed that, although the initiation of autophagy was normal, the steps involved in the decomposition of cellular waste were impaired in the absence of Ykt6.

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

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

“In short, we discovered YKT6 variants as the cause of a new developmental disorder that affects brain function and in certain cases also liver function, providing us with valuable information about 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,” added Dr. Bellen.


Texas Children’s Hospital

Diary reference:

Mother, M., and others. (2024). Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe childhood liver disease and risk of hepatocellular carcinoma. Genetics in Medicine. doi.org/10.1016/j.gim.2024.101125.

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