# SPTBN1

## Overview
SPTBN1 is a gene that encodes the protein spectrin beta, non-erythrocytic 1, commonly referred to as βII-spectrin. This protein is a crucial component of the cytoskeletal system, playing a vital role in maintaining cellular structure and stability across various cell types. βII-spectrin is characterized by its ability to form heterodimeric filamentous networks that support plasma membrane integrity and contribute to cellular functions such as signal transduction, membrane organization, and intracellular trafficking (Yang2021βII). The protein is involved in several key signaling pathways, including those regulating cell proliferation, survival, and development across different organ systems (Yang2021βII). Mutations in the SPTBN1 gene have been associated with a variety of diseases, including neurodevelopmental disorders and cancers, highlighting its significant role in human health and disease (Cousin2020Pathogenic; Yang2021βII).

## Structure
The SPTBN1 gene encodes the βII-spectrin protein, which is a multifunctional cytoskeletal protein characterized by a complex molecular structure. The primary structure of βII-spectrin consists of 2,364 amino acids, featuring multiple homologous tandem spectrin repeats, each composed of three antiparallel helices, which form a significant aspect of the protein's secondary structure (Rao2021β2-spectrin). These spectrin repeats are crucial for the protein's flexibility and elasticity, allowing it to maintain the structural integrity of plasma membranes.

At the tertiary structure level, βII-spectrin includes various functional domains such as a pair of calponin homology (CH) domains at the N-terminal side, which are involved in actin-binding, and a pleckstrin homology (PH) domain at the C-terminal side, which is important for membrane association and signal transduction (Rao2021β2-spectrin; Yang2021βII). The protein also contains an SH3 domain and various signaling motifs, contributing to its role in cellular signaling pathways (Yang2021βII).

The quaternary structure of βII-spectrin is organized into αβ dimers, which assemble side by side in an antiparallel manner. These dimers interact at their N-terminus and C-terminus to form tetramers, crucial for the formation of spectrin-actin networks that support plasma membrane integrity (Cousin2021Pathogenic).

βII-spectrin also exhibits post-translational modifications, including a CASPASE-3 cleavage site, which is relevant for its role in apoptosis (Rao2021β2-spectrin). Additionally, the protein has splice variants, notably the 'long' and 'short' C-terminal regions, which may influence its interaction with other cellular components and its functional diversity (Yang2021βII).

## Function
SPTBN1, also known as spectrin beta, non-erythrocytic 1, is a protein that plays a crucial role in maintaining cell structure and regulating various cellular functions. It is part of the spectrin family, which forms a heterodimeric filamentous network acting as a cytoplasmic scaffold for proteins, contributing to membrane integrity, organization, and trafficking (Yang2021βII). This protein is essential for the mechanical stability and elasticity of cells, influencing cell shape, flexibility, and intercellular contact. It is also implicated in maintaining genomic stability and has a role in the development of various organs, including the nerve, epithelium, inner ear, liver, and heart (Yang2021βII).

SPTBN1 is involved in critical signaling pathways such as the Phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt) pathway, significant for cell proliferation and survival, particularly in liver cells where it regulates cell proliferation and is vital for liver regeneration (Yang2021βII). Additionally, it interacts with the TGF-β/Smad and PI3K/AKT signaling pathways to control these processes (Yang2021βII).

In the context of cardiac function, SPTBN1, along with ankyrin B, forms a complex essential for the positioning and stability of ion channels and transporters such as Na/K-ATPase, Cav1.3, InsP3R, and NCX, playing a significant role in cardiac development (Yang2021βII). This complex is crucial during embryonic heart development, and its disruption can lead to defects such as abnormal cardiac muscle cell differentiation and cytoskeleton formation (Yang2021βII).

## Clinical Significance
Mutations in the SPTBN1 gene, which encodes βII-spectrin, are linked to a range of neurodevelopmental and neurological disorders. Pathogenic variants of this gene can cause a novel autosomal dominant neurodevelopmental syndrome characterized by developmental delays, intellectual disability, seizures, and features of autism spectrum disorder and attention deficit hyperactivity disorder (Cousin2020Pathogenic). These mutations disrupt neuronal architecture and function, impairing axonal growth and organelle transport, which are crucial for normal neuron function (Cousin2021Pathogenic).

In addition to neurological impacts, SPTBN1 mutations and alterations are implicated in various cancers. For instance, βII-spectrin is involved in ovarian and breast cancers, where it affects cell growth, migration, and drug resistance mechanisms (Yang2021βII). The gene is also associated with myeloproliferative diseases through a fusion with the PDGFRB gene, affecting the tyrosine kinase receptor's activity (Yang2021βII).

Furthermore, SPTBN1 plays a role in cardiovascular diseases. Mutations or alterations in βII-spectrin can lead to severe heart conditions, including congenital arrhythmia and heart failure, by affecting the structural integrity and electrical activity of myocardial cells (Yang2021βII). 

Overall, the clinical significance of SPTBN1 spans a broad spectrum of disorders, underscoring its importance in both neurological function and broader systemic diseases.

## Interactions
SPTBN1, also known as spectrin beta, non-erythrocytic 1, engages in various physical interactions with proteins and nucleic acids, influencing cellular functions and stability. It forms complexes with α-synuclein, influencing neurite outgrowth in dopaminergic neuronal cells by moderating excessive neurite branching when co-transfected in SH-SY5Y cells (Lee2012α-Synuclein). This interaction is further evidenced by co-immunoprecipitation assays confirming their interaction in N2a neuronal cells (Lee2012α-Synuclein).

SPTBN1 also interacts with PTTG1, a securin with oncogenic properties, in seminoma cells. This interaction inhibits the nuclear translocation of PTTG1, thereby impairing its oncogenic activity by anchoring it in the cytoplasm (Teveroni2023SPTBN1). The interaction varies across different seminoma cell lines, with the highest binding capability observed in TCAM2 cells, suggesting a role in modulating PTTG1's subcellular distribution and function in cancer progression (Teveroni2023SPTBN1).

Additionally, SPTBN1 is crucial for the homologous recombination pathway in DNA repair, activating Fancd2 through the SPTBN1/SMAD3 complex, essential for responding to DNA damage (Chen2019SPTBN1). These interactions highlight SPTBN1's role in cellular signaling, structural stability, and genomic integrity, impacting various biological processes and disease mechanisms.


## References


[1. (Lee2012α-Synuclein) Hak Joo Lee, Kyunghee Lee, and Hana Im. Α-synuclein modulates neurite outgrowth by interacting with sptbn1. Biochemical and Biophysical Research Communications, 424(3):497–502, August 2012. URL: http://dx.doi.org/10.1016/j.bbrc.2012.06.143, doi:10.1016/j.bbrc.2012.06.143. (41 citations) 10.1016/j.bbrc.2012.06.143](https://doi.org/10.1016/j.bbrc.2012.06.143)

[2. (Cousin2020Pathogenic) Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome (4 citations) 10.1101/2020.08.31.20184481](https://doi.org/10.1101/2020.08.31.20184481)

[3. (Chen2019SPTBN1) Shuyi Chen, Jiajia Li, Ping Zhou, and Xiuling Zhi. Sptbn1 and cancer, which links? Journal of Cellular Physiology, 235(1):17–25, June 2019. URL: http://dx.doi.org/10.1002/jcp.28975, doi:10.1002/jcp.28975. (29 citations) 10.1002/jcp.28975](https://doi.org/10.1002/jcp.28975)

[4. (Cousin2021Pathogenic) Margot A. Cousin, Blake A. Creighton, Keith A. Breau, Rebecca C. Spillmann, Erin Torti, Sruthi Dontu, Swarnendu Tripathi, Deepa Ajit, Reginald J. Edwards, Simone Afriyie, Julia C. Bay, Kathryn M. Harper, Alvaro A. Beltran, Lorena J. Munoz, Liset Falcon Rodriguez, Michael C. Stankewich, Richard E. Person, Yue Si, Elizabeth A. Normand, Amy Blevins, Alison S. May, Louise Bier, Vimla Aggarwal, Grazia M. S. Mancini, Marjon A. van Slegtenhorst, Kirsten Cremer, Jessica Becker, Hartmut Engels, Stefan Aretz, Jennifer J. MacKenzie, Eva Brilstra, Koen L. I. van Gassen, Richard H. van Jaarsveld, Renske Oegema, Gretchen M. Parsons, Paul Mark, Ingo Helbig, Sarah E. McKeown, Robert Stratton, Benjamin Cogne, Bertrand Isidor, Pilar Cacheiro, Damian Smedley, Helen V. Firth, Tatjana Bierhals, Katja Kloth, Deike Weiss, Cecilia Fairley, Joseph T. Shieh, Amy Kritzer, Parul Jayakar, Evangeline Kurtz-Nelson, Raphael A. Bernier, Tianyun Wang, Evan E. Eichler, Ingrid M. B. H. van de Laar, Allyn McConkie-Rosell, Marie T. McDonald, Jennifer Kemppainen, Brendan C. Lanpher, Laura E. Schultz-Rogers, Lauren B. Gunderson, Pavel N. Pichurin, Grace Yoon, Michael Zech, Robert Jech, Juliane Winkelmann, Adriana S. Beltran, Michael T. Zimmermann, Brenda Temple, Sheryl S. Moy, Eric W. Klee, Queenie K.-G. Tan, and Damaris N. Lorenzo. Pathogenic sptbn1 variants cause an autosomal dominant neurodevelopmental syndrome. Nature Genetics, 53(7):1006–1021, July 2021. URL: http://dx.doi.org/10.1038/s41588-021-00886-z, doi:10.1038/s41588-021-00886-z. (44 citations) 10.1038/s41588-021-00886-z](https://doi.org/10.1038/s41588-021-00886-z)

[5. (Rao2021β2-spectrin) Shuyun Rao, Xiaochun Yang, Kazufumi Ohshiro, Sobia Zaidi, Zhanhuai Wang, Kirti Shetty, Xiyan Xiang, Md. Imtaiyaz Hassan, Taj Mohammad, Patricia S. Latham, Bao-Ngoc Nguyen, Linda Wong, Herbert Yu, Yousef Al-Abed, Bibhuti Mishra, Michele Vacca, Gareth Guenigault, Michael E. D. Allison, Antonio Vidal-Puig, Jihane N. Benhammou, Marcus Alvarez, Päivi Pajukanta, Joseph R. Pisegna, and Lopa Mishra. Β2-spectrin (sptbn1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Science Translational Medicine, December 2021. URL: http://dx.doi.org/10.1126/scitranslmed.abk2267, doi:10.1126/scitranslmed.abk2267. (23 citations) 10.1126/scitranslmed.abk2267](https://doi.org/10.1126/scitranslmed.abk2267)

[6. (Teveroni2023SPTBN1) Emanuela Teveroni, Fiorella Di Nicuolo, Edoardo Vergani, Alessandro Oliva, Emanuele Pierpaolo Vodola, Giada Bianchetti, Giuseppe Maulucci, Marco De Spirito, Tonia Cenci, Francesco Pierconti, Gaetano Gulino, Federica Iavarone, Andrea Urbani, Domenico Milardi, Alfredo Pontecorvi, and Francesca Mancini. Sptbn1 mediates the cytoplasmic constraint of pttg1, impairing its oncogenic activity in human seminoma. International Journal of Molecular Sciences, 24(23):16891, November 2023. URL: http://dx.doi.org/10.3390/ijms242316891, doi:10.3390/ijms242316891. (0 citations) 10.3390/ijms242316891](https://doi.org/10.3390/ijms242316891)

[7. (Yang2021βII) Panyu Yang, Yanyan Yang, Pin Sun, Yu Tian, Fang Gao, Chen Wang, Tingyu Zong, Min Li, Ying Zhang, Tao Yu, and Zhirong Jiang. Βii spectrin (sptbn1): biological function and clinical potential in cancer and other diseases. International Journal of Biological Sciences, 17(1):32–49, 2021. URL: http://dx.doi.org/10.7150/ijbs.52375, doi:10.7150/ijbs.52375. (55 citations) 10.7150/ijbs.52375](https://doi.org/10.7150/ijbs.52375)