Since Bertrand Might was first diagnosed with NGLY1 deficiency in 2012, medical research around this extremely rare genetic condition has expanded. Unfortunately, Bertrand passed away in October 2020. However, his diagnosis spurred a desire to better understand this genetic disorder to benefit the additional 60 patients who have been discovered. But as patients have begun to be identified, a question emerged: why, despite sharing the same deactivated gene, do some patients experience more intense symptoms than others?

Ultimately, this line of questioning led to research which identified another potential gene which can exacerbated related symptoms. The research, led by geneticist Dr. Clement Chow, PhD, explored NGLY1 deficiency in fruit flies. According to NewsWise, this introduced Chow to ncc69, a fruit fly gene that modulates NGLY1 severity. In humans, the gene is known as NKCC1, and researchers determined that NGLY1 chemically modifies NKCC1. Could this be the answer everyone was looking for? Read the research findings published in eLife.

Fruit Fly Research

To begin the research, researchers used the Drosophila Genetic Reference Panel to sample 200 fruit flies who were each slightly genetically different than the rest. Next, they removed a functional NGLY1 gene for a non-functional copy. As described in the publication:

The resulting progeny showed a phenotypic spectrum from 0 to 100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease.

In short, some flies with a non-functional NGLY1 gene were able to live through adulthood, while this genetic mutation was nearly immediately lethal for others. After evaluating the genetics of surviving flies, and comparing the genetics to those who died, researchers created a list of potential gene candidates. NKCC1 was on this list.

Mice Studies

Next, researchers began exploring the intersection of NGLY1 and NKCC1 in mice models of the disorder. They found that glycosylation, which adds sugar molecules to protein, played a role in NKCC1 protein development. NGLY1, however, works to remove sugar molecules from specific proteins. In patients with NGLY1 deficiency, the non-functional NGLY1 was unable to remove excess sugar from proteins. As a result, NKCC1 was faced with too much extra sugar. As a result, NKCC1 became 50% less effective.

Additionally, researchers determined that NKCC1 plays a role in salivary gland, sweat gland, and tear duct function. Similar to how patients with NGLY1 deficiency are unable to make these bodily fluids, patients with NKCC1 deficiencies are also unable to make them. Therefore, both NKCC1 and NGLY1 may exacerbate the negative effects of the other.

NGLY1 Deficiency

According to NGLY1.org:

N-glycanase deficiency, or NGLY1 deficiency, is an extremely rare genetic disorder in which both copies of a patient’s NGLY1 gene contain mutations. This gene holds the information the body needs to synthesize the enzyme N-glycanase, [so as] a result of their genetic mutations, NGLY1 patients produce little or no N-glycanase.

Because of the small amount of patients and the burgeoning research, many signs and symptoms of this condition have yet to be identified. However, potential symptoms include:

• “Floppy” muscle tone
• Sleep apnea and/or disturbed sleep
• Auditory and peripheral neuropathy
• Difficulty speaking, crawling, swallowing, or walking
• Intellectual and developmental delays
• Seizures
• Liver dysfunction
• Microcephaly
• Small hands and feet
• Lack of tears and sweat
• Difficulty with temperature regulation
• Chronic dry eyes

Learn more about NGLY1 deficiency.