HQ Team
October 7, 2022: University of Michigan researchers have identified a new gene implicated in the lysosomal storage disorder disease, mucolipidosis type II. This disease causes edema of the internal organs and skeletal dysplasia.
The new gene, TMEM251, is necessary for lysosomes to function correctly. Children suffering from this disease barely passage 7.
Lysosomes are found in all cells except red blood cells and are responsible for recycling cell waste. When the lysosome does not function, then this garbage piles up in the cells.
The Michigan team, led by Ming Li, assistant professor of molecular, cellular and developmental biology, discovered that if TMEM251 is defective, it fails to find the correct pathway for the lysosomes to function. The study is published in Nature Communications.
The lysosomes have around 50 enzymes that do the recycling function of the garbage that cells produce. The enzymes recycle proteins, nucleic acid, carbohydrates and lipids back as usable material. But for these enzymes to travel inside the lysosome, they need a signal called the mannose-6-phosphate biosynthetic pathway, or M6P.
“It’s like a postage stamp. The enzymes have to have this signal in order to go inside the lysosome. If they don’t have M6P, they aren’t able to go into the lysosome,” Li said. “So consequently, you still have lysosomes, but not a single one of them would be functional because they lack these enzymes.”
CRISPR technique to isolate Lysosome gene
Li and his team studied the composition of lysosome membrane proteins and its breakdown process called ubiquitination. They also wanted to isolate the genes responsible for the functioning of lysosome. The team used a CRISPR technique to rule out each gene.
The experiment turned up TMEM251.
“So then the game became, why is this gene so important for human health? And why is it so critical for lysosomal function?” Li said.
TMEM251 gene encodes an enzyme that activates M6P, a pathway that most of the 50 digesting enzymes in the lysosomes require. Delving into previous research, the team discovered a 2021 paper that described mucolipidosis type II-like symptoms in humans that result from having a defective TMEM251 gene.
“Our discovery answered the molecular mechanism of this new human disease,” Li said.
The protein in gene TMEM251 activates another enzyme called GNPT, which catalyzes the M6P pathway.
The researchers then further experimented with a zebrafish by knocking out the TMEM251 gene in it. Comparing the results with a healthy zebrafish they found defects in the zebrafish’s abdomen, skeletal and cartilage development and heart.
Co-author Xi Yang said the team had a solution to combat the illness in humans. The therapy is in very early stages and is based on what they call an “enzyme replacement therapy.” The solution lies in supplying the enzyme which contains the M6P modification to TMEM251-deficient cells through endocytosis.
“We know that the pathogenesis of this disease is because you don’t have a functional lysosome,” said Yang, a research specialist in Li’s lab. “This knockout cell can actually use these endocytosed functional enzymes to rebuild their lysosome and make it functional again. You can rescue the deficiency, at least at a cellular level.”
The study can be accessed here.