Abstract
Spectrins are cytoskeletal proteins that are expressed ubiquitously in the mammalian nervous system. Pathogenic variants in SPTAN1, SPTBN1, SPTBN2 and SPTBN4, four of the six genes encoding neuronal spectrins, cause neurological disorders. Despite their structural similarity and shared role as molecular organizers at the cell membrane, spectrins vary in expression, subcellular localization and specialization in neurons, and this variation partly underlies non-overlapping disease presentations across spectrinopathies. Here, we summarize recent progress in discerning the local and long-range organization and diverse functions of neuronal spectrins. We provide an overview of functional studies using mouse models, which, together with growing human genetic and clinical data, are helping to illuminate the aetiology of neurological spectrinopathies. These approaches are all critical on the path to plausible therapeutic solutions.
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References
Bennett, V. & Lorenzo, D. N. An adaptable spectrin/ankyrin-based mechanism for long-range organization of plasma membranes in vertebrate tissues. Curr. Top. Membr. 77, 143–184 (2016).
Lorenzo, D. N. Cargo hold and delivery: ankyrins, spectrins, and their functional patterning of neurons. Cytoskeleton 77, 129–148 (2020).
Bennett, V. & Lorenzo, D. N. Spectrin- and ankyrin-based membrane domains and the evolution of vertebrates. Curr. Top. Membr. 72, 1–37 (2013).
Zhou, R., Han, B., Xia, C. & Zhuang, X. Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons. Science 365, 929–934 (2019).
Marchesi, V. T. & Steers, E. J. Selective solubilization of a protein component of the red cell membrane. Science 159, 203–204 (1968).
Winkelmann, J. C. et al. Full-length sequence of the cDNA for human erythroid β-spectrin. J. Biol. Chem. 265, 11827–11832 (1990).
Bennett, V., Davis, J. & Fowler, W. E. Brain spectrin, a membrane-associated protein related in structure and function to erythrocyte spectrin. Nature 299, 126–131 (1982).
Hu, R. J., Watanabe, M. & Bennett, V. Characterization of human brain cDNA encoding the general isoform of β-spectrin. J. Biol. Chem. 267, 18715–18722 (1992).
Berghs, S. et al. βIV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system. J. Cell Bio 151, 985–1002 (2000).
Hund, T. J. et al. A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J. Clin. Invest. 120, 3508–3519 (2010).
Stabach, P. R. & Morrow, J. S. Identification and characterization of βV spectrin, a mammalian ortholog of Drosophila βH spectrin. J. Biol. Chem. 275, 21385–21395 (2000).
Papal, S. et al. The giant spectrin βV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route. Hum. Mol. Genet. 22, 3773–3788 (2013).
Ohara, O., Ohara, R., Yamakawa, H., Nakajima, D. & Nakayama, M. Characterization of a new β-spectrin gene which is predominantly expressed in brain. Brain Res. Mol. Brain Res. 57, 181–192 (1998).
Stankewich, M. C. et al. A widely expressed βIII spectrin associated with Golgi and cytoplasmic vesicles. Proc. Natl Acad. Sci. USA 95, 14158–14163 (1998).
Wasenius, V. M. et al. Primary structure of the brain α-spectrin. J. Cell Bio. 108, 79–93 (1989).
Sahr, K. E. et al. The complete cDNA and polypeptide sequences of human erythroid α-spectrin. J. Biol. Chem. 265, 4434–4443 (1990).
Hayes, N. V. et al. Identification of a novel C-terminal variant of βII spectrin: two isoforms of βII spectrin have distinct intracellular locations and activities. J. Cell Sci. 113, 2023–2034 (2000).
Uemoto, Y. et al. Specific role of the truncated βIV-spectrin Sigma6 in sodium channel clustering at axon initial segments and nodes of Ranvier. J. Biol. Chem. 282, 6548–6555 (2007).
Grum, V. L., MacDonald, R. I. & Mondragón, A. Structures of two repeats of spectrin suggest models of flexibility. Cell 98, 523–535 (1999).
Ipsaro, J. J. et al. Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex. Blood 115, 4843–4852 (2010).
Speicher, D. W., Weglarz, L. & DeSilva, T. M. Properties of human red cell spectrin heterodimer (side-to-side) assembly and identification of an essential nucleation site. J. Biol. Chem. 267, 14775–14782 (1992).
Rief, M., Pascual, J., Saraste, M. & Gaub, H. E. Single molecule force spectroscopy of spectrin repeats: low unfolding forces in helix bundles. J. Mol. Biol. 286, 553–561 (1999).
Krieger, C. C. et al. Cysteine shotgun–mass spectrometry (CS-MS) reveals dynamic sequence of protein structure changes within mutant and stressed cells. Proc. Natl Acad. Sci. USA 108, 8269–8274 (2011).
Heidemann, S. R. & Bray, D. Tension-driven axon assembly: a possible mechanism. Front. Cell. Neurosci. 9, 316 (2015).
Šmít, D., Fouquet, C., Pincet, F., Zapotocky, M. & Trembleau, A. Axon tension regulates fasciculation/defasciculation through the control of axon shaft zippering. eLife 6, e19907 (2017).
Leterrier, C. & Pullarkat, P. A. Mechanical role of the submembrane spectrin scaffold in red blood cells and neurons. J. Cell Sci. 135, jcs259356 (2022).
Byers, T. J. & Branton, D. Visualization of the protein associations in the erythrocyte membrane skeleton. Proc. Natl Acad. Sci. USA 82, 6153–6157 (1985).
Gardner, K. & Bennett, V. Modulation of spectrin–actin assembly by erythrocyte adducin. Nature 328, 359–362 (1987).
Kuhlman, P. A., Hughes, C. A., Bennett, V. & Fowler, V. M. A new function for adducin. Calcium/calmodulin-regulated capping of the barbed ends of actin filaments. J. Biol. Chem. 271, 7986–7991 (1996).
Weber, A., Pennise, C. R., Babcock, G. G. & Fowler, V. M. Tropomodulin caps the pointed ends of actin filaments. J. Cell Biol. 127, 1627–1635 (1994).
Ursitti, J. A. & Fowler, V. M. Immunolocalization of tropomodulin, tropomyosin and actin in spread human erythrocyte skeletons. J. Cell Sci. 107, 1633–1639 (1994).
Pan, L., Yan, R., Li, W. & Xu, K. Super-resolution microscopy reveals the native ultrastructure of the erythrocyte cytoskeleton. Cell Rep. 22, 1151–1158 (2018).
Han, B., Zhou, R., Xia, C. & Zhuang, X. Structural organization of the actin–spectrin-based membrane skeleton in dendrites and soma of neurons. Proc. Natl Acad. Sci. USA 114, E6678–E6685 (2017).
Xu, K., Zhong, G. & Zhuang, X. Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science 339, 452–456 (2013).
Leterrier, C. Putting the axonal periodic scaffold in order. Curr. Opin. Neurobiol. 69, 33–40 (2021).
D’Este, E. et al. Subcortical cytoskeleton periodicity throughout the nervous system. Sci. Rep. 6, 22741 (2016).
He, J. et al. Prevalent presence of periodic actin–spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species. Proc. Natl Acad. Sci. USA 113, 6029–6034 (2016).
Zhong, G. et al. Developmental mechanism of the periodic membrane skeleton in axons. eLife 3, e04581 (2014).
Hofmann, M. et al. Cytoskeletal assembly in axonal outgrowth and regeneration analyzed on the nanoscale. Sci. Rep. 12, 14387 (2022).
Leite, S. C. et al. The actin-binding protein α-adducin is required for maintaining axon diameter. Cell Rep. 15, 490–498 (2016).
Lorenzo, D. N. et al. βII-Spectrin promotes mouse brain connectivity through stabilizing axonal plasma membranes and enabling axonal organelle transport. Proc. Natl Acad. Sci. USA 116, 15686–15695 (2019).
Cousin, M. A. et al. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nat. Genet. 53, 1006–1021 (2021).
Hammarlund, M., Jorgensen, E. M. & Bastiani, M. J. Axons break in animals lacking β-spectrin. J. Cell Biol. 176, 269–275 (2007).
Law, R. et al. Cooperativity in forced unfolding of tandem spectrin repeats. Biophys. J. 84, 533–544 (2003).
Dubey, S. et al. The axonal actin–spectrin lattice acts as a tension buffering shock absorber. eLife 9, e51772 (2020).
Wang, T. et al. Radial contractility of actomyosin rings facilitates axonal trafficking and structural stability. J. Cell Biol. 219, e201902001 (2020).
Costa, A. R. et al. The membrane periodic skeleton is an actomyosin network that regulates axonal diameter and conduction. eLife 9, e55471 (2020).
Galiano, M. R. et al. A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell 149, 1125–1139 (2012).
Albrecht, D. et al. Nanoscopic compartmentalization of membrane protein motion at the axon initial segment. J. Cell Biol. 215, 37–46 (2016).
Qu, Y., Hahn, I., Webb, S. E., Pearce, S. P. & Prokop, A. Periodic actin structures in neuronal axons are required to maintain microtubules. Mol. Biol. Cell 28, 296–308 (2017).
Lacas-Gervais, S. et al. βIVΣ1 spectrin stabilizes the nodes of Ranvier and axon initial segments. J. Cell Biol. 166, 983–990 (2004).
Huang, C. Y. et al. αII spectrin forms a periodic cytoskeleton at the axon initial segment and is required for nervous system function. J. Neurosci. 37, 11311–11322 (2017).
Leterrier, C. et al. Nanoscale architecture of the axon initial segment reveals an organized and robust scaffold. Cell Rep. 13, 2781–2793 (2015).
Komada, M. & Soriano, P. βIV-Spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J. Cell Biol. 156, 337–348 (2002).
Yang, Y., Ogawa, Y., Hedstrom, K. L. & Rasband, M. N. βIV spectrin is recruited to axon initial segments and nodes of Ranvier by ankyrinG. J. Cell Biol. 176, 509–519 (2007).
Yang, R. et al. Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly. Proc. Natl Acad. Sci. USA 116, 19717–19726 (2019).
Jenkins, P. M. et al. Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc. Natl Acad. Sci. USA 112, 957–964 (2015).
Liu, C. H. et al. β spectrin-dependent and domain specific mechanisms for Na+ channel clustering. eLife 9, e56629 (2020).
Ho, T. S.-Y. et al. A hierarchy of ankyrin–spectrin complexes clusters sodium channels at nodes of Ranvier. Nat. Neurosc. 17, 1664–1672 (2014).
Rasband, M. N. & Peles, E. Mechanisms of node of Ranvier assembly. Nat. Rev. Neurosci. 22, 7–20 (2021).
D’Este, E., Kamin, D., Gottfert, F., El-Hady, A. & Hell, S. W. STED nanoscopy reveals the ubiquity of subcortical cytoskeleton periodicity in living neurons. Cell Rep. 10, 1246–1251 (2015).
D’Este, E., Kamin, D., Balzarotti, F. & Hell, S. W. Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy. Proc. Natl Acad. Sci. USA 114, E191–E199 (2017).
Yoshimura, T., Stevens, S. R., Leterrier, C., Stankewich, M. C. & Rasband, M. N. Developmental changes in expression of βIV spectrin splice variants at axon initial segments and nodes of Ranvier. Front. Cell. Neurosci. 10, 304 (2016).
Liu, C. H. et al. Nodal β spectrins are required to maintain Na+ channel clustering and axon integrity. eLife 9, e52378 (2020).
Ogawa, Y. et al. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. J. Neurosci. 26, 5230–5239 (2006).
Amor, V. et al. The paranodal cytoskeleton clusters Na+ channels at nodes of Ranvier. eLife 6, e21392 (2017).
Zhang, C., Susuki, K., Zollinger, D. R., Dupree, J. L. & Rasband, M. N. Membrane domain organization of myelinated axons requires βII spectrin. J. Cell Biol. 203, 437–443 (2013).
Huang, C. Y.-M., Zhang, C., Zollinger, D. R., Leterrier, C. & Rasband, M. N. An αII spectrin-based cytoskeleton protects large-diameter myelinated axons from degeneration. J. Neurosci. 37, 11323–11334 (2017).
Bär, J., Kobler, O., van Bommel, B. & Mikhaylova, M. Periodic F-actin structures shape the neck of dendritic spines. Sci. Rep. 6, 37136 (2016).
Sidenstein, S. C. et al. Multicolour multilevel STED nanoscopy of actin/spectrin organization at synapses. Sci. Rep. 6, 26725 (2016).
Lorenzo, D. N. et al. A PIK3C3–ankyrin-B–dynactin pathway promotes axonal growth and multiorganelle transport. J. Cell Biol. 207, 735–752 (2014).
Stankewich, M. C. et al. Targeted deletion of βIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. Proc. Natl Acad. Sci. USA 107, 6022–6027 (2010).
Efimova, N. et al. βIII spectrin is necessary for formation of the constricted neck of dendritic spines and regulation of synaptic activity in neurons. J. Neurosci. 37, 6442–6459 (2017).
Armbrust, K. R. et al. Mutant β-III spectrin causes mGluR1α mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5. J. Neurosci. 34, 9891–9904 (2014).
Ikeda, Y. et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat. Genet. 38, 184–190 (2006).
Wechsler, A. & Teichberg, V. I. Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J. 17, 3931–3939 (1998).
Lambert, S. & Bennett, V. Postmitotic expression of ankyrinR and β R-spectrin in discrete neuronal populations of the rat brain. J. Neurosci. 13, 3725–3735 (1993).
Malchiodi-Albedi, F., Ceccarini, M., Winkelmann, J. C., Morrow, J. S. & Petrucci, T. C. The 270 kDa splice variant of erythrocyte β-spectrin (βI Σ2) segregates in vivo and in vitro to specific domains of cerebellar neurons. J. Cell Sci. 106, 67–78 (1993).
Fifková, E. & Morales, M. Actin matrix of dendritic spines, synaptic plasticity, and long-term potentiation. Int. Rev. Cytol. 139, 267–307 (1992).
Sytnyk, V., Leshchyns’ka, I., Nikonenko, A. G. & Schachner, M. NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J. Cell Biol. 174, 1071–1085 (2006).
Ursitti, J. A. et al. Spectrins in developing rat hippocampal cells. Brain Res. Dev. Brain Res. 129, 81–93 (2001).
Nestor, M. W., Cai, X., Stone, M. R., Bloch, R. J. & Thompson, S. M. The actin binding domain of βI-spectrin regulates the morphological and functional dynamics of dendritic spines. PLoS One 6, e16197 (2011).
Smith, K. R. et al. Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses. Neuron 84, 399–415 (2014).
Lorenzo, D. N. et al. Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila. J. Cell Biol. 189, 143–158 (2010).
Cheney, R., Hirokawa, N., Levine, J. & Willard, M. Intracellular movement of fodrin. Cell Motil. 3, 649–655 (1983).
Takeda, S. et al. Kinesin superfamily protein 3 (KIF3) motor transports fodrin-associating vesicles important for neurite building. J. Cell Biol. 148, 1255–1265 (2000).
Holleran, E. A. et al. βIII spectrin binds to the Arp1 subunit of dynactin. J. Biol. Chem. 276, 36598–36605 (2001).
Muresan, V. et al. Dynactin-dependent, dynein-driven vesicle transport in the absence of membrane proteins: a role for spectrin and acidic phospholipids. Mol. Cell 7, 173–183 (2001).
He, M., Abdi, K. M. & Bennett, V. Ankyrin-G palmitoylation and βIIspectrin binding to phosphoinositide lipids drive lateral membrane assembly. J. Cell Biol. 206, 273e288 (2014).
Hyvönen, M. et al. Structure of the binding site for inositol phosphates in a PH domain. EMBO J. 14, 4676–4685 (1995).
Sikorski, A. F., Terlecki, G., Zagon, I. S. & Goodman, S. R. Synapsin I-mediated interaction of brain spectrin with synaptic vesicles. J. Cell Biol. 114, 313–318 (1991).
Stankewich, M. C. et al. Cell organization, growth, and neural and cardiac development require αII-spectrin. J. Cell Sci. 124, 3956–3966 (2011).
Wang, Y. et al. Critical roles of αII spectrin in brain development and epileptic encephalopathy. J. Clin. Invest. 128, 760–773 (2018).
Beijer, D. et al. Nonsense mutations in α-II spectrin in three families with juvenile onset hereditary motor neuropathy. Brain 142, 2605–2616 (2019).
Dong, H. L., Chen, L. & Wu, Z. Y. A novel de novo SPTAN1 nonsense variant causes hereditary motor neuropathy in a Chinese family. Brain 144, e11 (2021).
Ylikallio, E. et al. De novo SPTAN1 mutation in axonal sensorimotor neuropathy and developmental disorder. Brain 143, 6–8 (2020).
Miazek, A. et al. Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity. Sci. Rep. 11, 7312 (2021).
Van de Vondel, L. et al. De novo and dominantly inherited SPTAN1 mutations cause spastic paraplegia and cerebellar ataxia. Mov. Disord. https://doi.org/10.1002/mds.28959 (2022).
Tang, Y. et al. Disruption of transforming growth factor-β signaling in ELF β-spectrin-deficient mice. Science 299, 574–577 (2003).
Liu, Y. et al. Critical role of spectrin in hearing development and deafness. Sci. Adv. 5, eaav7803 (2019).
Rosenfeld, J. A. et al. Heterozygous variants in SPTBN1 cause intellectual disability and autism. Am. J. Med. Genet. A. 185, 2037–2045 (2021).
Jackson, M. et al. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410, 89–93 (2001).
Clarkson, Y. L. et al. β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations. Hum. Mol. Genet. 23, 3875–3882 (2014).
Perkins, E. M. et al. Loss of β-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J. Neurosci. 30, 4857–4867 (2010).
Lise, S. et al. Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development. PLoS Genet. 8, e1003074 (2012).
Clarkson, Y. L., Gillespie, T., Perkins, E. M., Lyndon, A. R. & Jackson, M. β-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from the Golgi. Hum. Mol. Genet. 19, 3634–3641 (2010).
Parolin Schnekenberg, R. et al. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain 138, 1817–1832 (2015).
Jacob, F. D., Ho, E. S., Martinez-Ojeda, M., Darras, B. T. & Khwaja, O. S. Case of infantile onset spinocerebellar ataxia type 5. J. Child. Neurol. 28, 1292–1295 (2013).
Nuovo, S. et al. Between SCA5 and SCAR14: delineation of the SPTBN2 p.R480W-associated phenotype. Eur. J. Hum. Genet. 26, 928–929 (2018).
Nicita, F. et al. Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia. Clin. Genet. 96, 169–175 (2019).
Mizuno, T. et al. Infantile-onset spinocerebellar ataxia type 5 associated with a novel SPTBN2 mutation: a case report. Brain Dev. 41, 630–633 (2019).
Romaniello, R. et al. Novel SPTBN2 gene mutation and first intragenic deletion in early onset spinocerebellar ataxia type 5. Ann. Clin. Transl. Neurol. 8, 956–963 (2021).
Sancho, P. et al. Expanding the β-III spectrin-associated phenotypes toward non-progressive congenital ataxias with neurodegeneration. Int. J. Mol. Sci. 22, 2505 (2021).
Parkinson, N. J. et al. Mutant β-spectrin 4 causes auditory and motor neuropathies in quivering mice. Nat. Genet. 29, 61–65 (2001).
Wang, C. C. et al. βIV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy. Am. J. Hum. Genet. 102, 1158–1168 (2018).
Yang, Y. et al. βIV spectrins are essential for membrane stability and the molecular organization of nodes of Ranvier. J. Neurosci. 24, 7230–7240 (2004).
Devaux, J. J. The C-terminal domain of βIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier. J. Physiol. 588, 4719–4730 (2010).
Stevens, S. R. et al. Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K+ channels. eLife 10, e66491 (2021).
Stankewich, M. C. et al. Outer hair cell function is normal in βV spectrin knockout mice. Hear. Res. 423, 108564 (2022).
Saitsu, H. et al. Dominant-negative mutations in α-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am. J. Hum. Genet. 86, 881–891 (2010).
Writzl, K. et al. Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation. Epilepsia 53, e106–e110 (2012).
Hamdan, F. F. et al. Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy. Eur. J. Med. Genet. 20, 796–800 (2012).
Nonoda, Y. et al. Progressive diffuse brain atrophy in West syndrome with marked hypomyalination due to SPTAN1 gene mutation. Brain Dev. 35, 280–283 (2013).
Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
Ream, M. A. & Mikati, M. A. Clinical utility of genetic testing in pediatric drug-resistant epilepsy: a pilot study. Epilepsy Behav. 37, 241–248 (2014).
Yavarna, T. et al. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum. Genet. 134, 967–980 (2015).
Tohyama, J. et al. SPTAN1 encephalopathy: distinct phenotypes and genotypes. J. Hum. Genet. 60, 167–173 (2015).
Retterer, K. et al. Clinical application of whole-exome sequencing across clinical indications. Genet. Med 18, 696–704 (2016).
Stavropoulos, D. J. et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom. Med. 1, 15012 (2016).
Syrbe, S. et al. Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy. Brain 140, 2322–2336 (2017).
Rapaccini, V. et al. A child with a c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 mutation associated with a severe early infantile epileptic encephalopathy. Int. J. Mol. Sci. 19, 1976 (2018).
Terrone, G. et al. Intrafamilial variability in SPTAN1-related disorder: from benign convulsions with mild gastroenteritis to developmental encephalopathy. Eur. J. Paediatr. Neurol. 28, 237–239 (2020).
Leveille, E. et al. SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia. J. Hum. Genet. 64, 1145–1151 (2019).
Xie, F., Chen, S., Liu, P., Chen, X. & Luo, W. SPTAN1 variants likely cause autosomal recessive complicated hereditary spastic paraplegia. J. Hum. Genet. 67, 165–168 (2021).
Gartner, V. et al. Novel variants in SPTAN1 without epilepsy: an expansion of the phenotype. Am. J. Med. Genet. 176, 2768–2776 (2018).
Marco Hernández, A. V. et al. Extending the clinical phenotype of SPTAN1: from DEE5 to migraine, epilepsy, and subependymal heterotopias without intellectual disability. Am. J. Med. Genet. A. 188, 147–159 (2022).
Luongo-Zink, C. et al. Longitudinal neurodevelopmental profile of a pediatric patient with de novo SPTAN1, epilepsy, and left hippocampal sclerosis. Epilepsy Behav. Rep. 19, 100550 (2022).
Satterstrom, F. K. et al. Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants. Nat. Neurosci. 22, 1961–1965 (2019).
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
Cho, E. & Fogel, B. L. A family with spinocerebellar ataxia type 5 found to have a novel missense mutation within a SPTBN2 spectrin repeat. Cerebellum 12, 162–164 (2013).
Bian, X. et al. Two novel missense variants in SPTBN2 likely associated with spinocerebellar ataxia type 5. Neurol. Sci. 42, 5195–5203 (2021).
Wang, Y. et al. A Japanese SCA5 family with a novel three-nucleotide in-frame deletion mutation in the SPTBN2 gene: a clinical and genetic study. J. Hum. Genet. 59, 569–573 (2014).
Zonta, A., Brussino, A., Dentelli, P. & Brusco, A. A novel case of congenital spinocerebellar ataxia 5: further support for a specific phenotype associated with the p.(Arg480Trp) variant in SPTBN2. BMJ Case Rep. 13, e238108 (2020).
Valentino, F. et al. Exome sequencing in 200 intellectual disability/autistic patients: new candidates and atypical presentations. Brain Sci. 11, 936 (2021).
Accogli, A. et al. Heterozygous missense pathogenic variants within the second spectrin repeat of SPTBN2 lead to infantile-onset cerebellar ataxia. J. Child. Neurol. 35, 106–110 (2019).
Yıldız Bölükbaşı, E. et al. Progressive SCAR14 with unclear speech, developmental delay, tremor, and behavioral problems caused by a homozygous deletion of the SPTBN2 pleckstrin homology domain. Am. J. Med. Genet. A. 173, 2494–2499 (2017).
Al-Muhaizea, M. A. et al. A novel homozygous mutation in SPTBN2 leads to spinocerebellar ataxia in a consanguineous family: report of a new infantile-onset case and brief review of the literature. Cerebellum 17, 276–285 (2018).
Fogel, B. L. et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 71, 1237–1246 (2014).
Elsayed, S. M. et al. Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations. Eur. J. Hum. Genet. 22, 286–288 (2014).
Liu, L. Z. et al. A novel missense mutation in the spectrin β nonerythrocytic 2 gene likely associated with spinocerebellar ataxia type 5. Chin. Med. J. 129, 2516–2517 (2016).
Rea, G., Tirupathi, S., Williams, J., Clouston, P. & Morrison, P. J. Infantile onset of spinocerebellar ataxia type 5 (SCA-5) in a 6 month old with ataxic cerebral palsy. Cerebellum 19, 161–163 (2020).
Spagnoli, C. et al. Infantile-onset spinocerebellar ataxia type 5 (SCA5) with optic atrophy and peripheral neuropathy. Cerebellum 20, 481–483 (2021).
Ranum, L. P. W., Schut, L. J., Lundgren, J. K., Orr, H. T. & Livingston, D. M. Spinocerebellar ataxia gene type 5 in a family descended from the paternal grandparents of President Lincoln maps to chromosome 11. Nat. Genet. 8, 280–284 (1994).
Stevanin, G., Herman, A., Brice, A. & Durr, A. Clinical and MRI findings in spinocerebellar ataxia type 5. Neurology 53, 1355–1357 (1999).
Burk, K. et al. Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred. Neurology 62, 327–329 (2004).
Sun, M. et al. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. Genet. Med. 21, 195–206 (2019).
Avery, A. W., Crain, J., Thomas, D. D. & Hays, T. S. A human β-III-spectrin spinocerebellar ataxia type 5 mutation causes high-affinity F-actin binding. Sci. Rep. 6, 21375 (2016).
Knierim, E. et al. A recessive mutation in β-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness. Hum. Genet. 136, 903–910 (2017).
Häusler, M. G. et al. A novel homozygous splice-site mutation in the SPTBN4 gene causes axonal neuropathy without intellectual disability. Eur. J. Med. Genet. 63, 103826 (2020).
Buelow, M. et al. Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum. Eur. J. Hum. Genet. 29, 1121–1128 (2021).
Belkheir, A. M. et al. Severe form of βIV-spectrin deficiency with mitochondrial dysfunction and cardiomyopathy—a case report. Front. Neurol. 12, 643805 (2021).
Anazi, S. et al. Expanding the genetic heterogeneity of intellectual disability. Hum. Genet. 136, 1419–1429 (2017).
Pehlivan, D. et al. The genomics of arthrogryposis, a complex trait: candidate genes and further evidence for oligogenic inheritance. Am. J. Hum. Genet. 105, 132–150 (2019).
Avery, A. W. et al. Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation. Nat. Commun. 8, 1350 (2017).
Creighton, B. A. et al. Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor sema 3A. eLife 10, e69815 (2021).
Khan, A. et al. SPTBN5, encoding the βV-spectrin protein, leads to a syndrome of intellectual disability, developmental delay, and seizures. Front. Mol. Neurosci. 15, 877258 (2022).
Berghs, S. et al. Autoimmunity to βIV spectrin in paraneoplastic lower motor neuron syndrome. Proc. Natl Acad. Sci. USA 98, 6945–6950 (2001).
Bartley, C. M. et al. βIV-Spectrin autoantibodies in 2 individuals with neuropathy of possible paraneoplastic origin: a case series. Neurol. Neuroimmunol. Neuroinflamm. 9, e1188 (2022).
Sanchez-Mut, J. V. et al. DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease. Brain 136, 3018–3027 (2013).
Hüls, A. et al. Newborn differential DNA methylation and subcortical brain volumes as early signs of severe neurodevelopmental delay in a South African Birth Cohort Study. World J. Biol. Psychiatry. 1–12 (2022).
Sihag, R. K. & Cataldo, A. M. Brain β-spectrin is a component of senile plaques in Alzheimer’s disease. Brain Res. 743, 249–257 (1996).
Czogalla, A. & Sikorski, A. F. Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells. Cell Mol. Life Sci. 62, 1913–1924 (2005).
Leverenz, J. B. et al. Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathol. 17, 139–145 (2007).
Peuralinna, T. et al. Genome-wide association study of neocortical Lewy-related pathology. Ann. Clin. Transl. Neurol. 2, 920–931 (2015).
Ordonez, D. G., Lee, M. K. & Feany, M. B. α-Synuclein induces mitochondrial dysfunction through spectrin and the actin cytoskeleton. Neuron 97, 108–124 (2018).
Susuki, K. et al. Glial βII spectrin contributes to paranode formation and maintenance. J. Neurosci. 38, 6063–6075 (2018).
Neniskyte, U. & Gross, C. T. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat. Rev. Neurosci. 18, 658–670 (2017).
Patel, D. C., Tewari, B. P., Chaunsali, L. & Sontheimer, H. Neuron–glia interactions in the pathophysiology of epilepsy. Nat. Rev. Neurosci. 20, 282–297 (2019).
Lukens, J. R. & Eyo, U. B. Microglia and neurodevelopmental disorders. Annu. Rev. Neurosci. 45, 225–245 (2022).
Saifetiarova, J., Shi, Q., Paukert, M., Komada, M. & Bhat, M. A. Reorganization of destabilized nodes of Ranvier in βIV spectrin mutants uncovers critical timelines for nodal restoration and prevention of motor paresis. J. Neurosci. 38, 6267–6282 (2018).
Whiteley, J. T. et al. Reaching into the toolbox: stem cell models to study neuropsychiatric disorders. Stem Cell Rep. 17, 187–210 (2022).
Rinaldi, C. & Wood, M. J. A. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat. Rev. Neurol. 14, 9–21 (2018).
Acknowledgements
The authors apologize to those colleagues whose work could not be cited because of space limitations. This work was supported by National Institute of Mental Health (NIMH) grant R01MH127848 and National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS110810.
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Glossary
- Axon initial segment
-
(AIS). The domain 20–60 μm long at the proximal axon–soma interface that has a high density of voltage-gated ion channels and other membrane proteins responsible for the initiation of the action potential.
- De novo variants
-
Changes in the sequence of a gene that are seen for the first time in an individual but are not present in the parents.
- Gain-of-function
-
A missense mutation (altered amino acid sequence) that results in enhanced or abnormal protein function.
- Haploinsufficient
-
A gene for which 50% of normal protein expression is insufficient for normal function and may result in disease.
- Juxtaparanode
-
A region adjacent to each side of a paranode in myelinated axons.
- Knock-in mouse
-
A mouse in which an endogenous gene sequence of interest is altered by a one-for-one substitution with a transgene or by adding gene sequences that are not found within the locus.
- Knockout mouse
-
A mouse in which expression of a gene of interest is inactivated.
- Loss-of-function
-
A mutation that abolishes protein function, often by partial or complete loss of protein expression.
- Nodes of Ranvier
-
(NoR). Ion channel-rich gaps along a myelinated axon that expose the neuronal membrane to the extracellular space and speed up the propagation of the action potential along the axon.
- Paranode
-
A region adjacent to each edge of nodes of Ranvier (NoR) in myelinated axons.
- Pinceaux terminals
-
The terminals of the Pinceau, a paintbrush-like network of cerebellar basket cell axon branchlets embracing the axon initial segment (AIS) of Purkinje neurons.
- Postsynaptic density
-
(PSD). The protein-dense molecular network located beneath the membrane of dendritic spines of excitatory neurons.
- Probands
-
The first individuals in a family who are suspected to be at risk of or affected by a genetic condition.
- Somatodendritic
-
A neuronal region that includes the cell body and dendrites but excludes the axon.
- Spectrinopathies
-
Diseases associated with loss or aberrant function of spectrins.
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Lorenzo, D.N., Edwards, R.J. & Slavutsky, A.L. Spectrins: molecular organizers and targets of neurological disorders. Nat Rev Neurosci 24, 195–212 (2023). https://doi.org/10.1038/s41583-022-00674-6
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DOI: https://doi.org/10.1038/s41583-022-00674-6
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