Just as you cannot stand or move without bones, each neuron has its own skeletal scaffold made of interconnected protein tubes that can give it shape, transport goods, and allow it to move.
The SPTBN1 gene encodes βII-Spectrin protein, which is the building block of a micron-scale network structure located below the neuron membrane. When this network is defective in mice, brain neurons will be confused, young mice will not be able to reach developmental landmarks, and adult mice will behave abnormally.
Scientists have now identified 29 people with mutations in one of their two SPTNB1 genes, and they exhibit developmental, language and motor delays, mild to severe mental retardation, autism symptoms, seizures, behavioral and motor abnormalities , Low muscle tone and abnormal facial morphology.
A global collaborative research team led by scientists from the University of North Carolina at Chapel Hill has shown that these human SPTBN1 variant proteins cannot lock their molecular partners, which will damage the stability, organization and dynamics of neuronal β-spectrin scaffolds.
These findings were published in an article in Nature Genetics that pathogenic SPTBN1 variants cause autosomal dominant neurodevelopmental syndrome. The research was funded by the Mayo Clinic Center for Individualized Medicine, the National Ataxia Foundation, and the National Institutes of Health (NIH).
The author points out that the study defines SPTBN1 variants as the genetic basis of neurodevelopmental syndrome (spectrin disease) and emphasizes the important function of βII-spectrin in the nervous system. This research is the first step in finding a cure for this disease and provides new genetic insights into how the brain functions.
Dr. Margot Cousin, a translational genomics researcher at the Mayo Clinic Individualization Center, said: "This gene can now be used for genetic testing of people suspected of having neurodevelopmental disorders, which may end the diagnostic odysseys endured by these people and their families." The main author of medicine and the study. "Although there is no specific treatment for patients with SPTBN1-related diseases, we can now provide patients with answers to the root cause of the disease. This is the most important first step in finding a cure."
Cousin said that most genetic variants in SPTNB1 are not inherited, but occur in affected patients.
"We have demonstrated the effects of these variants on the function of the protein encoded by SPTBN1 through a variety of different model systems, including computational protein modeling, human and mouse cell-based systems, patient-derived cell systems, and in vivo mouse studies. Genes," Cousin said.
"Some variants behave very differently from others. Some of them destabilize βII spectrin, while others disrupt its ability to interact importantly with other proteins. These differences in functional effects explain our experience in patients Observed clinical variability."
Under the current standard of care, many neurodevelopmental diseases are still undiagnosed, which poses a major challenge for rare disease genome research, but Cousin believes that the trend is changing.
Clinical variability, especially when the sample size is small, can be difficult to determine whether the symptom profile may be caused by a single gene mutation.
"However, this gene has many of the characteristics of a rare single-gene disease gene, including that there is no mutation in SPTBN1 in normal people, other spectrin genes can cause neurological syndrome, and the study of mice lacking this protein has serious flaws. "Cousin explained.
Cousin said that cell-based and animal models developed in research will continue to be of invaluable value in advancing knowledge of disease mechanisms and testing potential treatments.
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