Variants in SPTBN1 Associated with Neurodevelopmental Disorder

Variants in SPTBN1 are responsible for a specific neurodevelopmental disorder, according to researchers from the Mayo Clinic. They say their study, published in Nature Genetics, is a first step in finding a potential therapeutic strategy for this disorder, and it increases the number of genes known to be associated with conditions that affect how the brain functions.

SPTBN1 encodes βII-spectrin, which “forms micrometer-scale networks associated with plasma membranes” the researchers write. “Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies.” These phenotypes, they say, suggest, “that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function.”

“The gene can now be included in genetic testing for people suspected of having a neurodevelopmental disorder, which may end the diagnostic odyssey these people and their families have endured,” says Margot Cousin, PhD, a translational genomics researcher in Mayo Clinic’s Center for Individualized Medicine and the study’s lead author.

For the global study, a collaboration with The University of North Carolina at Chapel Hill, researchers investigated disease-causing variants of the SPTBN1 gene in 29 people with clinical neurodevelopmental symptoms, including language and motor delays, intellectual disability, autistic features, seizures, behavioral and movement abnormalities, and variable dysmorphic facial features. Overall, the team identified 28 unique variants.

Cousin says most of the genetic variants were not inherited, but rather newly occurred in the patients who were affected.

“We showed through multiple different model systems, including computational protein modeling, human- and mouse cell-based systems, patient-derived cell systems, and in vivo mouse studies, the impact the variants have on the function of the protein encoded by the SPTBN1 gene,” Cousin explains. “I had a hunch this gene was the answer for these patients, but it wasn’t until we accrued and studied more patients with variants in SPTBN1 that we could see how the variants had damaging effects on the protein and we could begin putting the story together.”

SPTBN1 codes for a protein called beta-two spectrin, which is abundantly expressed in the brain and other parts of the body. Beta-two spectrin makes protein networks within cells, and it is essential for the brain’s development and connectivity.

“Interestingly, some of the variants behave very differently than the others, where some make the beta-two spectrin protein unstable and some disrupt its ability to make important interactions with other proteins,” Cousin says. “But these differences in functional effects helped to explain the clinical variability we were observing in the patients.”

The study also demonstrates the challenges in rare disease genomics, as many neurodevelopmental diseases remain undiagnosed under the standard of care.

“The clinical variability we observed in people early on was not very compelling that this could be a single genetic condition,” she explains. “The gene, however, had many of the hallmarks of a rare monogenic disease gene, including that the normal population doesn’t have variation in SPTBN1, other spectrin genes cause neurological syndromes, and mouse studies completely lacking the protein have severe defects.”

Cousin says the cell-based and animal models developed in the study will continue to be invaluable in advancing knowledge of the disease mechanisms and testing any potential therapeutic strategies.  “While there is not yet a specific treatment available for people affected by SPTBN1-associated disease, we can now provide patients with an answer to the root cause of disease, which is the most important first step toward finding a cure.”

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