Scientists at the University of North Carolina at Chapel Hill School of Medicine and their colleagues have demonstrated that variants of the SPTBN1 gene can alter neuronal architecture, dramatically affecting their function and leading to a rare and newly defined neurodevelopmental syndrome in children.
Damaris Lorenzo, PhD, assistant professor in the Department of Cell Biology at UNC and member of the UNC Neuroscience Center at the UNC School of Medicine, led this research, which was published today in the journal Genetics of nature. Lorenzo, who is also a member of the UNC Research Center on Intellectual and Developmental Disabilities (IDDRC) at the UNC School of Medicine, is the lead author.
The SPTBN1 gene tells neurons and other cell types how to make βII-spectrin, a multi-functional protein in the nervous system. Children with these variants may suffer from delayed speech and motor skills, as well as intellectual disability. Some patients received an additional diagnosis, such as autism spectrum disorder, ADHD, and epilepsy. Identifying the genetic variants that cause this wide range of disabilities is the important first step in finding treatments for this syndrome.
Lorenzo first learned of patients with complex neurodevelopmental presentations and carriers of SPTBN1 variants from Queenie Tan, MD, PhD, medical geneticist, and Becky Spillmann, MS, genetic counselor – both members of the network site. NIH-funded undiagnosed diseases (UDN) at Duke University and co-authors of the Genetics of nature paper. They connected with Margot Cousin, PhD, geneticist associated with the UDN site of the Mayo Clinic and co-first author of the study. Cousin had also collected clinical information from carriers of SPTBN1 variants. Other clinical genetics teams took note of these efforts and joined the study.
The cohort of individuals affected by the SPTBN1 variants continues to grow. Lorenzo and his colleagues have been contacted about new cases after publishing a preprint of their initial findings last summer. Identifying the genetic cause of rare diseases such as SPTBN1 syndrome requires pooling the knowledge of multiple patients to establish common clinical and biological patterns.
Fortunately, the advent of affordable gene sequencing technology, as well as the creation of databases and networks to facilitate information sharing between clinicians and researchers, has significantly accelerated the diagnosis of rare diseases, said Lorenzo. “To put our case in a historical perspective, βII-spectrin was co-discovered 40 years ago through pioneering work involving my colleagues at UNC Keith Burridge, PhD, and Richard Cheney, PhD, as well as my postdoctoral mentor Vann Bennett, PhD, at Duke. However, his association with the disease has eluded us so far. “
ΒII-spectrin is closely associated with the neuronal cytoskeleton – a complex network of filamentous proteins that spans the neuron and plays a central role in their growth, shape and plasticity. ΒII-spectrin forms an extensive scaffolding network that ensures the mechanical integrity of membranes and helps orchestrate the correct positioning of molecular complexes within the neuron. Through research published in PNAS in 2019, Lorenzo discovered that II-spectrin is essential for normal brain wiring in mice and for the proper transport of organelles and vesicles in axons – the long stretches that carry signals from neurons to other neurons. ΒII-spectrin is an integral part of the process that allows neurons to develop, maintain and function normally.
In this new study, Lorenzo’s research team has shown that at the biochemical level, the genetic variants identified in patients are sufficient to cause protein aggregation, an aberrant association of βII-spectrin with the cytoskeleton, alter the transport and the growth of axonal organelles, and alter the morphology of neurons. These impairments can permanently alter the way neurons connect and communicate with each other, which would contribute to the aetiology of neurodevelopmental disorders. The team showed that reducing βII-spectrin levels only in neurons disrupts structural connectivity between cortical areas in mutant mice, a deficit also seen in brain MRIs of some patients.
Working with Sheryl Moy, PhD, professor in the Department of Psychiatry at UNC and director of the Mouse Behavioral Phenotyping (MBP) Core at UNC IDDRC, the researchers found that these mice exhibited developmental and behavioral deficits consistent with the presentations. observed in humans.
“Now that we have established the methods to ascribe the probability of pathogenicity to the SPTBN1 variants and to determine how they modify neurons, our immediate goal is to learn more about the molecular and cellular mechanisms and brain circuits affected, and to assess strategies for potential clinical interventions, ”said Lorenzo.
To this end, her team will collaborate with Adriana Beltran, PhD, Assistant Professor in the Department of Genetics at UNC and Director of the UNC Human Pluripotent Cell Core, to use neurons differentiated from patient-induced pluripotent stem cells. And the research team will continue to exploit the predictions of molecular modeling in collaboration with Brenda Temple, PhD, professor in the Department of Biochemistry and Biophysics at UNC and Director of the Core of Structural Bioinformatics at UNC, both. co-authors of Genetics of nature paper.
“As a basic science researcher, it’s so satisfying to use knowledge and tools to provide answers to patients,” said Lorenzo. “I first witnessed this thrill of scientific discovery and collaborative work as a graduate student 15 years ago, when our lab identified the genetic cause of the first spectrinopathy affecting the nervous system.
This work was the discovery of variants in a different gene of spectrin as the cause of squamous cell ataxia type 5 (SCA5), led by Laura Ranum, PhD, who was at the time at the University of Minnesota. In the follow-up work, as a member of this team, Lorenzo provided information on the pathogenic mechanism of SCA5.
“In addition to immediate relevance to affected patients, information from our work on SPTNB1 syndrome will inform findings in other complex disorders with overlapping pathologies,” said Lorenzo. “It is exciting to be a part of such important work with a team of dedicated scientists and clinicians.”
The members of the Lorenzo lab who are co-authors of the Genetics of nature the papers are co-lead author Blake Creighton, research technician at the Lorenzo lab; Reggie Edwards, graduate student; Keith Breau, graduate 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 contributors and co-authors of the UNC-Chapel Hill article are Kathryn Harper, PhD, project manager at MBP Core; and Lorena Munoz and Alvaro Beltran, both research associates at hHPSC.
University of North Carolina Health Care
Cousin, MA, et al. (2021) Pathogenic variants of SPTBN1 cause autosomal dominant neurodevelopmental syndrome. Genetics of nature. doi.org/10.1038/s41588-021-00886-z.