Rapaccini V, Miconi F, Esposito S, Pasini A. Pathogenetic Potential of the Mutations of SPTAN 1. J Human Clin Gen. (2019);1(1):1-2 Journal of Human & Clinical Genetics Mini Review Open Access

Pathogenetic Potential of the Mutations of SPTAN 1 Valentina Rapaccini1,2, Francesco Miconi3,4, Susanna Esposito5, Augusto Pasini1,2 1Child Neurology and Psychiatry Unit, Systems Medicine Department, University Hospital Tor Vergata, Viale Oxford 81, Rome, Italy 2Unità Sanitaria Locale (USL) Umbria 2, Viale VIII Marzo, Terni, Italy 3Paediatric Section, Università degli Studi di Perugia, Perugia, Italy 4Paediatric Clinic, Azienda Ospedaliera di Terni, Terni, Italy 5Department of Surgical and Biomedical Sciences, Paediatric Clinic, Università degli Studi di Perugia, Perugia, Italy

Recent evidence demonstrates that mutations in numerous Article Info such as SPTAN1 are responsible for early-onset epileptic Article Notes encephalopathies, previously considered as cryptogenic1. SPTAN1, Received: January 3, 2019 Accepted: February 18, 2019 *Correspondence: located on 9q34.11 , encodes a subtype of an α Dr. Valentina Rapaccini, Child Neurology and Psychiatry that is specifically expressed in nonerythrocytic cells. are Unit, Systems Medicine Department, University Hospital stabilize the plasma membrane and organize intracellular organelles. Tor Vergata, Viale Oxford 81, Rome, Italy; Email: a large family of filamentous cytoskeletal that contribute to [email protected].

©2019 Rapaccini V. This article is distributed under the terms of alsoThey implicated consist of αin and other β dimers cellular that functions form tetramers including linked DNA repair in a head- and the Creative Commons Attribution 4.0 International License. cellto-head cycle arrangement. regulation. The specific encoded by SPTAN1 in As mentioned above, mutations of SPTAN1 are considered responsible for early infantile epileptic encephalopathies and alternate splicing of this results in multiple transcript

altering the sensibility of voltage-gated sodium channels, can determinevariants. Inan particularelevated action specific potential in-frame threshold mutation that is of implicated SPTAN1, in the generation of early epileptic events2. This effect is due to an

assembledabnormal aggregationin an antiparallel of α-II side mutant/β-II by side manner and α-II/β-IIIinto heterodimers spectrin thatheterodimers. can form end-to-endIn fact, α-II tetramers spectrin consists integrating of α into and the β subunits, membrane is

. Recently in mouse models it has been shown that αII spectrin is aspectsubiquitously of nervous expressed development in rodent and and synaptogenesis human somatodendritic and supporting and aaxonal dominant-negative domains suggesting mechanism that αII of spectrin SPTAN1 is mutations involved in in critical early infancy epileptic encephalopathy3. Currently, genetic analysis demonstrated that mutations in the

associations, can compromise heterodimer formation between thelast two two spectrins. spectrin repeats, It has been required demonstrated for α/β spectrin that only heterodimer in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal

phenotypes4. region can lead to dominant negative effects and severe specific SPTAN1 mutations are associated with various neurodevelopmental phenotypes, ranging from mild to severe and progressive. The typical clinical manifestations are often characterized by epileptic encephalopathy with seizures,

Page 1 of 2 Rapaccini V, Miconi F, Esposito S, Pasini A. Pathogenetic Potential of the Mutations of SPTAN 1. J Journal of Human and Clinical Genetics Human Clin Gen (2019);1(1):2-2 hypsarrhythmia, poor visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual be predicted by two different methods: the Combined disability, in addition to brainstem and cerebellar atrophy The functional impact of the identified variants can and cerebral hypomyelination, that can be evaluated by variant ensemble learner (REVEL) scoring systems. CADD magnetic resonance imaging. The most severe mutations Annotation Dependent Depletion (CADD) and Rare exome typically cause early onset epileptic encephalopathy one metric by contrasting variants that survived natural characterized by infantile spasms or tonic seizures5. selectionis a framework with simulated integrating mutations multiple based annotations upon all possible into nucleotide variants. The higher the CADD score the more Imaging studies suggested that the severity of neurological impairment and epileptic phenomena in SPTAN 1 mutations is in most cases highly predictive of correlates with structural abnormalities and with both pathogenicitylikely the variant8. REVEL has deleterious is an ensemble effects; method the score predicting obtained mutation type and location. Moreover, this clinical picture the pathogenicity of missense variants with the possibility is often related to Early Onset West Syndrome, a common to distinguish pathogenic from rare neutral variants. The infantile epileptic syndrome that in some cases can be 9. associated with SPTAN1 mutation6. In particular, according to a recent study7, the vast Referenceshigher the score the more likely the variant is pathogenic 1. Distinct phenotypes and genotypes, Journal of Human epilepsy and in particular, in the subjects who suffered Tohyama J, Nakashima M, Nabatame S, et al. SPTAN1 encephalopathy: frommajority an earlyof patients infantile affected epileptic by SPTAN1encephalopathy mutation infantile, exhibit 2. Genetics.Saitsu H, 2015;Tohyama 60: J,167–173. Kumada doi:10.1038/jhg.2015.5. T, et al. Dominant-negative mutations spasms were the most prominent seizure type represented. in alpha-II spectrin cause West syndrome with severe cerebral Infantile spasms manifested at a median age of 4 months hypomyelination, spastic quadriplegia, and developmental delay. (ranging from neonatal onset to 9 months) and occurred ajhg.2010.04.013. Epub 2010 May 20. Am J Hum Genet. 2010 Jun 11; 86(6): 881-91. doi: 10.1016/j. as part of West syndrome accompanied by hypsarrhythmia 3. in the context of an infantile epileptic encephalopathy or on EEG. They generally persisted and also were highly Wang Y, Ji T, Nelson AD, et al. Critical roles of αII spectrin in brain refractory to treatment. Hypotonia were also present and development and epileptic encephalopathy. J Clin Invest. 2018 Feb 1; could be considered an early sign of abnormal development. 4. 128(2): 760-773. doi: 10.1172/JCI95743. Epub 2018 Jan 16. in-frame de novo mutation in SPTAN1 in intellectual disability and In general, most individuals with infantile epileptic Hamdan FF, Saitsu H, Nishiyama K, et al. Identification of a novel with quadriplegia and absent speech, often accompained pontocerebellar atrophy. Eur J Hum Genet. 2012 Jul; 20(7): 796-800. 5. doi:Ioannidis 10.1038/ejhg.2011.271. NM, Rothstein JH, EpubPejaver 2012 V, Janet al. 18. REVEL: An Ensemble encephalopathy exhibit profound developmental delay Method for Predicting the Pathogenicity of Rare Missense Variants.

ajhg.2016.08.016. Epub 2016 Sep 22. by lack of visual contact and movement disorder, such as Am J Hum Genet. 2016 Oct 6; 99(4): 877-885. doi: 10.1016/j. opisthotonicTherefore, posturing as mentioned or dyskinetic above, phenotypes movements. associated 6. with SPTAN1 mutations are various, ranging from mild to cerebral hypomyelination and reduced cerebral white matter. Brain severe and progressive. In particular, spectrin aggregate Tohyama J, Akasaka N, Osaka H, et al. Early onset West syndrome with 7. Dev.Syrbe 2008 S, Harms May; 30(5): FL, Parrini 349-55. E, Epubet al. 2007Delineating Dec 11. SPTAN1 associated heterodimerization domain seems to be associated with phenotypes: from isolated epilepsy to encephalopathy with aformation severe neurodegenerative in fibroblasts with course mutations and suggests in thethat a/bthe stretch from Asp2303 to Met2309 in the a20 progressive brain atrophy. Brain. 2017 Sep 1; 140(9): 2322-2336. 8. doi: 10.1093/brain/awx195. the relative pathogenicity of human genetic variants. Nature Genetics. Kircher M, Witten DM, Jain P, et al. A general framework for estimating differentrepeat is importantin-frame SPTAN1 for a/b spectrin heterodimer formation 9. 2014; 46(3): 310. inand/or association aII spectrin with different function. clinical Moreover, features, recently from four a milder variant characterized mutations by generalized have been epilepsy identified with Writzl K, Primec ZR, Stražišar BG, et al. Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl pontocerebellar atrophy to severe phenotypes, generally with SPTAN1 mutation. Epilepsia. 2012 Jun; 53(6): e106-10. doi: associated with in-frame SPTAN1 mutations in the last two 10.1111/j.1528-1167.2012.03437.x. Epub 2012 Mar 1. spectrin repeats in the C-terminal region.

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