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

Gut microbiome shaped by dietary sphingolipids
Journal News

Gut microbiome shaped by dietary sphingolipids

September 22, 2020

A new tracing method described in the Journal of Lipid Research offers clues on how a macronutrient interacts with the microbes that live inside us.

From the journals: JBC
Journal News

From the journals: JBC

September 21, 2020

Proteases that fire up the flu. A sulfate pocket to take out MRSA. Proteins that prompt cancer protrusions. Read about recent papers on these topics and more.

AeroNabs promise powerful, inhalable protection against COVID-19
News

AeroNabs promise powerful, inhalable protection against COVID-19

September 20, 2020

As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease.

Keeping bone and muscle strong on the ISS
News

Keeping bone and muscle strong on the ISS

September 19, 2020

Researchers helped mice stay mighty with an experiment to counter the effects of microgravity. The gene treatment might also enhance muscle and bone health on Earth — and in humans.

Understanding the impact of Type 1 diabetes susceptibility genes
Research Spotlight

Understanding the impact of Type 1 diabetes susceptibility genes

September 17, 2020

Starting in eighth grade, a series of mentors who saw something special in Sharifa Love–Rutledge helped her stay on the path to being a researcher — and becoming a mentor to others.

Re-creating coagulation in a lab
Journal News

Re-creating coagulation in a lab

September 15, 2020

Threatened arthropods are in the crossfire of medical and conservation efforts, but new research could benefit horseshoe crabs and humans alike.