Rare CACNA1A mutations leading to congenital ataxia

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• dc.contributor.author Izquierdo Serra, Mercè
• dc.contributor.author Fernández-Fernández, José Manuel, 1967-
• dc.contributor.author Serrano, Mercedes L.
• dc.date.accessioned 2022-02-01T07:32:37Z
• dc.date.available 2022-02-01T07:32:37Z
• dc.date.issued 2020
• dc.description.abstract Human mutations in the CACNA1A gene that encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 (P/Q-type) Ca2+ channel cause multiple neurological disorders including sporadic and familial hemiplegic migraine, as well as cerebellar pathologies such as episodic ataxia, progressive ataxia, and early-onset cerebellar syndrome consistent with the definition of congenital ataxia (CA), with presentation before the age of 2 years. Such a pathological role is in accordance with the physiological relevance of CaV2.1 in neuronal tissue, especially in the cerebellum. This review deals with the report of the main clinical features defining CA, along with the presentation of an increasing number of CACNA1A genetic variants linked to this severe cerebellar disorder in the context of Ca2+ homeostasis alteration. Moreover, the review describes each pathological mutation according to structural location and known molecular and cellular functional effects in both heterologous expression systems and animal models. In view of this information in correlation with the clinical phenotype, we take into consideration different pathomechanisms underlying the observed motor dysfunction in CA patients carrying CACNA1A mutations. Present therapeutic management in CA and options for the development of future personalized treatment based on CaV2.1 dysfunction are also discussed.
• dc.description.sponsorship This work was funded by the Spanish Ministry of Science and Innovation, the State Research Agency (AEI, Agencia Estatal de Investigación), and FEDER Funds (Fondo Europeo de Desarrollo Regional): Grants RTI2018-094809-B-I00 to J.M.F.F. and CEX2018-000792-M through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”. M.S. is supported by the Generalitat de Catalunya (PERIS SLT008/18/00194) and National Grant PI17/00101 from the National R&D&I Plan, cofinanced by the Instituto de Salud Carlos III (Subdirectorate-General for Evaluation and Promotion of Health Research) and European Regional Development Fund. M.I.-S. holds a “Juan de la Cierva-Incorporación” Fellowship funded by the Spanish Ministry of Science and Innovation.
• dc.format.mimetype application/pdf
• dc.identifier.citation Izquierdo-Serra M, Fernández-Fernández JM, Serrano M. Rare CACNA1A mutations leading to congenital ataxia. Pflugers Arch. 2020;472(7):791-809. DOI: 10.1007/s00424-020-02396-z
• dc.identifier.doi http://dx.doi.org/10.1007/s00424-020-02396-z
• dc.identifier.issn 0031-6768
• dc.identifier.uri http://hdl.handle.net/10230/52376
• dc.language.iso eng
• dc.publisher Springer
• dc.relation.ispartof Pflugers Arch. 2020;472(7):791-809
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094809-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
• dc.rights © Springer The final publication is available at Springer via http://dx.doi.org/10.1007/s00424-020-02396-z.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword CACNA1A gene
• dc.subject.keyword CaV2.1 (P/Q-type) voltage-dependent calcium channel
• dc.subject.keyword Cerebellar atrophy
• dc.subject.keyword Congenital ataxia
• dc.subject.keyword Early-onset cerebellar signs
• dc.subject.keyword Permanent ataxia
• dc.title Rare CACNA1A mutations leading to congenital ataxia
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion