Just as you could not stand tall or move without your bony frame, each neuron has its own skeletal scaffold of interconnected tubes of protein that gives it shape, traffics cargo, and allows it to move.

The SPTBN1 gene encodes the βII-spectrin protein, that is a building block in the micrometer-scale meshwork that lies right under the neuronal membrane. When this meshwork is defective in mice, cerebral neurons are in disarray, pups do not reach developmental landmarks, and the adult mice display behavioral abnormalities.

Scientists have now identified 29 individuals with mutations in one of their two SPTNB1 genes, who exhibit developmental, language and motor delays, mild to severe intellectual disability, autistic symptoms, seizures, behavioral and movement abnormalities, low muscle tone and abnormalities in facial morphology.

The global team of collaborating researchers led by scientists at the University of North Carolina at Chapel Hill show that these human SPTBN1 variant proteins are unable to latch on to their molecular partners which disrupts the stability, organization and dynamics of the neuronal β-spectrin scaffold.

These findings are published in the Nature Genetics article, Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. The study was funded by the Center for Individualized Medicine at the Mayo Clinic, the National Ataxia Foundation, and the US National Institutes of Health (NIH).

The authors note that the study defines SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome (spectrinopathy) and underscores the important function of βII-spectrin in the nervous system. This study is the first step in finding a treatment for the disorder and provides new genetic insights into how the brain functions.

Margot Cousin, PhD, is a translational genomics researcher at the Mayo Clinic Center for Individualized Medicine and is lead author on this study

“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. “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.”

Most of the SPTNB1 genetic variants were not inherited, but rather occurred in the affected patients, says Cousin.

“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,” says Cousin.

“Some of the variants behave very differently than the others, where some make the βII spectrin protein unstable and some disrupt its ability to make important interactions with other proteins. These differences in functional effects explain the clinical variability we were observing in the patients.”

Many neurodevelopmental diseases remain undiagnosed under the current standard of care, posing a significant challenge in rare disease genomic research but Cousin believes the tide is turning.

Clinical variability, particularly when the sample size is small, can make it difficult to ascertain whether the spectrum of symptoms can arise from mutations in a single gene.

“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 explains.

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 potential treatments.