Scientists from the University of North Carolina at Chapel Hill School of Medicine and colleagues have shown that variants in the SPTBN1 gene can alter neural architecture, dramatically affect its function, and lead to a rare, newly defined neural development syndrome in children.
Damaris Lorenzo, PhD, assistant professor in the UNC’s Department of Cell Biology and a member of the UNC Neuroscience Center at the UNC School of Medicine, led this research, which was published in the journal today Natural genetics. Lorenzo, who is also a member of the UNC Intellectual and Developmental Disabilities Research Center (IDDRC) at the UNC School of Medicine, is the lead author.
The SPTBN1 gene instructs neurons and other cell types to make Î²II-spectrin, a protein with multiple functions in the nervous system. Children wearing these variants may experience speech and motor delays, as well as intellectual disabilities. Some patients have received additional diagnoses such as autism spectrum disorder, ADHD, and epilepsy. Identifying the genetic variants that cause this wide range of disabilities is the first major milestone in identifying treatments for this syndrome.
Lorenzo first found out about patients with complex neurological presentations who carried SPTBN1 variants from Queenie Tan, MD, PhD, a medical geneticist, and Becky Spillmann, MS, a genetic counselor – both members of the NIH-funded Undiagnosed Disease Network (UDN) in Duke University and co-authors of the Natural genetics Paper. They linked up with Margot Cousin, PhD, a geneticist linked to the Mayo Clinic’s UDN site and co-lead author of the study. Cousin had also collected clinical information from carriers of the SPTBN1 variant. Other clinical genetics teams learned about this effort and participated in the study.
The cohort of people affected by SPTBN1 variants continues to grow. Lorenzo and colleagues were contacted about new cases after they published a preprint of their first results last summer. Identifying the genetic cause of rare diseases such as SPTBN1 syndrome requires pooling the knowledge of several patients to establish common clinical and biological patterns.
“Fortunately, the advent of affordable gene sequencing technology, along with the creation of databases and networks to facilitate the exchange of information between clinicians and researchers, has accelerated the diagnosis of rare diseases tremendously,” said Lorenzo. “To put our case in a historical perspective, Î²II-spectrin was discovered 40 years ago through pioneering work by my UNC colleagues Keith Burridge, PhD, and Richard Cheney, PhD, and my postdoctoral mentor Vann Bennett, PhD, at . Duke were involved. However, the association with diseases has escaped us so far. “
Î²II-spectrin is closely linked to the neuronal cytoskeleton – a complex network of filamentous proteins that spans the neuron and plays a central role in its growth, shape and plasticity. Î²II-spectrin forms an extensive scaffold that gives membranes mechanical integrity and helps orchestrate the correct positioning of molecular complexes throughout the neuron. Through research published in PNAS in 2019, Lorenzo found that Î²II-spectrin was essential for normal brain wiring in mice and for the proper transport of organelles and vesicles in axons – the long extensions that carry signals from neurons to other neurons is. Î²II-spectrin is an integral part of the process that enables normal development, maintenance and function of neurons.
In this new study, Lorenzo’s research team showed that, at the biochemical level, the genetic variants identified in patients are sufficient to cause protein aggregation, an abnormal association of Î²II-spectrin with the cytoskeleton, the transport and growth of axonal organelles, and to change the morphology change of neurons. These deficiencies can permanently change the way neurons connect and communicate with one another, which is believed to contribute to the etiology of neurodevelopmental disorders. The team showed that reductions in Î²II-spectrin levels only in neurons disrupted structural connectivity between cortical areas in mutant mice, a deficit that has also been seen on brain MRIs in some patients.
Working with Sheryl Moy, PhD, professor at UNC’s Department of Psychiatry and director of the UNC IDDRC’s Mouse Behavioral Phenotyping (MBP) Core, the researchers found that these mice had developmental and behavioral deficits that were observed with those seen in humans Presentations match.
Now that we have established the methods for assigning the likelihood of pathogenicity to SPTBN1 variants and determining how they alter neurons, our immediate goal is to learn more about the molecular and cellular mechanisms and brain circuits involved, and strategies for potential clinical interventions to rate. “
Damaris Lorenzo, PhD, Assistant Professor, UNC Department of Cell Biology
To this end, her team will work with Adriana Beltran, PhD, assistant professor in the UNC’s Department of Genetics and director of the UNC’s Human Pluripotent Cell Core, to use neurons differentiated from patient-derived induced pluripotent stem cells. And the research team will work with Brenda Temple, PhD, professor in the UNC’s Department of Biochemistry and Biophysics and Director of the UNC Structural Bioinformatics Core, both co-authors of the Natural genetics Paper.
“As a basic research investigator, it’s so rewarding to use knowledge and tools to provide answers to patients,” said Lorenzo. “I first experienced this thrill of scientific discovery and collaboration as a PhD student 15 years ago when our lab identified the genetic cause of the first spectinopathy affecting the nervous system, and it has been a powerful motivator ever since.”
That work was the discovery of variants in another spectrin gene causing spinocellular ataxia type 5 (SCA5), led by Laura Ranum, PhD, who was at the University of Minnesota at the time. As part of this team, Lorenzo contributed to discoveries about the pathogenic mechanism of SCA5.
“Aside from being of immediate relevance to affected patients, insights from our work on SPTNB1 syndrome will provide insights into other complex diseases with overlapping pathologies,” said Lorenzo. “It’s exciting to be part of such important work with a team of dedicated scientists and clinicians.”
Members of the Lorenzo Laboratory who are co-authors in the Natural genetics Papers are co-lead author Blake Creighton, laboratory research technician in the Lorenzo laboratory; Reggie Edwards, PhD student; Keith Breau, PhD student at the time of this research; Deepa Ajit, PhD, postdoctoral fellow; Sruthi Dontu, Simone Afriyie and Julia Bay, all students at UNC-Chapel Hill; and Liset Falcon, laboratory research technician at the time of this research. Other UNC Chapel Hill contributors and co-authors of the paper include Kathryn Harper, PhD, project manager in the MBP Core; and Lorena Munoz and Alvaro Beltran, both research assistants at the hHPSC.