Study in Flies Reveals Interaction Between Genes Drives Severity of Ultra Rare Disease

Rare Daily Staff

Many genetic rare diseases are thought of as being caused by a disruption to a single gene, but despite the same underlying cause, people with the same genetic disease can have significant variance in the severity of their condition.

That’s the case with NGLY1 deficiency, an ultra-rare genetic disorder with less than 100 known patients. The disease affects every system of the body and is characterized by low muscle tone, seizures, developmental delays, and an inability to produce tears.

Clement Chow, a geneticist and assistant professor in the Department of Human Genetics at University of Utah Health, who studies NGLY1 deficiency in fruit fly models, sought to understand the wide variance in NGLY1 by seeking out other genes that interact with culprit NGLY1 gene.

In a paper published in eLife, Chow reports that his lab has found one gene that interacts with NGLY1 moderates the severity of the disease. The gene, ncc69, has a human counterpart called NKCC1. Chow showed that NGLY1 chemically modifies NKCC1. The work suggests studying this interaction could help illuminate how NGLY1 deficiency affects the body.

To search for genes that work together with NGLY1, the researchers needed flies with varied genetic backgrounds. To approximate the natural genetic diversity found in humans, Chow turned to a resource called the Drosophila Genetic Reference Panel, a collection of 200 different fruit fly lines.

In each strain of flies, Chow and his research team swapped in a non-working copy of the NGLY1 gene, then looked for differences in survival. They found the flies’ genetic background influenced how long the young flies could survive without NGLY1.

“These flies all carry the same disease mutation that’s supposed to cause the same disease,” Chow says. “Yet here we’re seeing that, in some genetic backgrounds, they can’t live at all with NGLY1 deficiency. And in some genetic backgrounds, all the flies survived to adulthood.”

After identifying a list of candidate genes, the researchers zeroed in on NKCC1 and to better understand how it interacts with NGLY1, the researchers moved to study to the two genes in mice.

In cells from mice, the researchers discovered that the NKCC1 protein assumes its correct shape through glycosylation, a chemical process that tacks sugar molecules onto the protein. NGLY1 acts to remove these sugar molecules from specific targets.

In the absence of NGLY1, Chow found, NKCC1 was overloaded with extra sugars, reducing activity in the cell by 50 percent. Without NGLY1, NKCC1 can’t do its job properly, which is to move fluids and ions out of the cell.

One of the hallmark features of NGLY1 deficiency is the inability to make tears, sweat, and saliva. It turns out that patients who lack NKCC1 also have this symptom. NKCC1 is active in salivary glands, sweat glands, and tear ducts, which supports the idea that the molecule plays a role in causing the symptoms.

“This was all discovered through a genetic screen in Drosophila,” Chow says. “This really speaks to the power of using simpler model organisms, especially for rare diseases, where you want to get results faster.”

Photo: Clement Chow, a geneticist and assistant professor in the Department of Human Genetics at University of Utah Health