Journal News

JBC: A causal gene for X-linked intellectual disability

Dawn Hayward
June 01, 2017

Intellectual disability affects between 1 percent and 3 percent of the world’s population. People with X-linked intellectual disability, a heritable condition, present with IQs below 70 and can be mildly or severely handicapped, requiring lifelong care.

The Human Genome Project greatly has facilitated the diagnosis of XLID, and more than 120 genes on the X chromosome have been established as causal for the disease, which primarily affects males.

A recent study in the Journal of Biological Chemistry reports a new causal gene for XLID. The study was conducted by a team of scientists led by Charles Schwartz at the Greenwood Genetic Center in South Carolina and Lance Wells at the University of Georgia.

The family

JBC-A-causal-gene-x-linked-Thumb480x270.png Greenwood Genetic Center

The Greenwood Genetic Center serves patients with birth defects, intellectual disability and autism. There, the Schwartz laboratory works with families with histories of XLID and analyzes genetic defects associated with the disease. For the study published in JBC, individuals from the genetics center traveled to Utah to obtain blood samples from a family with members with XLID in order to isolate DNA and generate cell lines.

DNA sequencing of affected family members uncovered many genes with single-nucleotide changes residing on the X chromosome. After looking for variants that resided in the coding region and that resulted in corresponding amino-acid changes, the Schwartz group came across a mutation in an enzyme called O-GlcNAc transferase, or OGT.

The OGT gene variant found in the Utah family had the three characteristics necessary for continued study: It segregated with the disease, contained a single amino-acid change in the protein and was expressed in the brain. That’s when the collaboration with glycobiologist Wells became critical.

The enzymes

OGT is an enzyme that adds a sugar molecule — GlcNAc — to nuclear and cytosolic proteins. Wells’ group studies this glycosylation modification. The enzyme that removes GlcNAc is called O-GlcNAcase, or OGA. Together, OGT and OGA influence the activity of many cytoplasmic and nuclear proteins in the cell.

The Utah family’s variant contained a leucine-to-phenylalanine substitution, which can be difficult for a protein to accommodate given that phenylalanaine is larger than leucine. The substitution resides in a region of OGT responsible for protein-protein interactions.

Biochemical experiments spearheaded by first author Krithika Vaidyanathan in the Wells laboratory revealed the Utah family’s mutant to be unstable. However, its enzymatic activity was normal, and O-GlcNAc levels, surprisingly, remained constant in patient cell lines derived from blood samples. These findings prompted studies of OGA, the enzyme responsible for removing the modification.

The researchers found that the OGT variant in affected males, along with other co-repressor proteins, occupy the promoter region of the OGA gene and reduce its transcription. This compensates for the OGT variant’s instability and maintains the O-GlcNAc glycosylation modification level.

The Wells laboratory then wondered if the OGT variant occupied other promoter regions too. So the group sequenced RNA of affected males to see which genes’ expression differed from controls’. The researchers found significant changes in several genes, and they’re currently investigating them.

The takeaways

Schwartz notes that the Utah family’s OGT gene variant was challenging to narrow down in the beginning of the work and emphasizes that the collaboration with Wells was critical to establishing OGT’s importance.

Wells points out that the RNA-sequencing experiment involved related patients, which raised the possibility of the results segregating by generation instead of disease. Fortunately, this was not the case.

The researchers say their future studies will investigate additional OGT gene mutations, recently identified by Schwartz and other clinical geneticists, that segregate with the disease. Both the Wells and Schwartz labs are looking at their effects on OGT function. The researchers also are studying stem-cell-derived neuronal cells that are affected by OGT gene mutations.

In the end, the JBC study represents the first instance of an OGT gene mutation being responsible for XLID and broadens the pathways involved in brain development and cognitive function.

Dawn Hayward

Dawn Hayward earned a Ph.D. in biochemistry from the Johns Hopkins University School of Medicine

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Brain Injury Awareness Month 2021
Health Observance

Brain Injury Awareness Month 2021

March 01, 2021

In the U.S., about 2.8 million people sustain a traumatic brain injury annually. Learn about recent research on TBI-related dementia, dysfunctional mitochondria and other work powering the march toward better therapies.

The evolution of proteins from mysteries to medicines
Essay

The evolution of proteins from mysteries to medicines

February 27, 2021

An essay in observance of National Protein Day.

'Every experiment and every breakthrough matters'
Health Observance

'Every experiment and every breakthrough matters'

February 26, 2021

An interview with NYMC dean Marina K. Holz, who studies a rare disease that affects women of childbearing age.

Progeria: From the unknown to the first FDA-approved treatment
Health Observance

Progeria: From the unknown to the first FDA-approved treatment

February 25, 2021

Hutchinson–Gilford progeria syndrome is a rare, fatal genetic disease that causes premature aging.

Raising awareness and funding for Pompe disease
Health Observance

Raising awareness and funding for Pompe disease

February 25, 2021

Father-turned-advocate has founded multiple organizations to support families and search for better therapies for people with rare lysosomal storage disorder.

A novel approach to septic shock leads to a prospective new therapy
Journal News

A novel approach to septic shock leads to a prospective new therapy

February 23, 2021

A French research team finds new evidence supporting endotoxin removal for treating life-threatening inflammation.