CACNA1A mutations causing early onset ataxia: profiling clinical, dysmorphic and structural-functional findings

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• dc.contributor.author Martínez Monseny, Antonio Federico
• dc.contributor.author Edo, Albert
• dc.contributor.author Casas Alba, Dídac
• dc.contributor.author Izquierdo Serra, Mercè
• dc.contributor.author Bolasell, Mercè
• dc.contributor.author Conejo, David
• dc.contributor.author Martorell, Loreto
• dc.contributor.author Muchart, Jordi
• dc.contributor.author Carrera, Laura
• dc.contributor.author Ortez, Carlos
• dc.contributor.author Nascimento, Andrés
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Fernández-Fernández, José Manuel, 1967-
• dc.contributor.author Serrano Masip, Mercedes
• dc.date.accessioned 2021-06-04T07:10:33Z
• dc.date.available 2021-06-04T07:10:33Z
• dc.date.issued 2021
• dc.description.abstract The CACNA1A gene encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 Ca2+ channel, essential in neurotransmission, especially in Purkinje cells. Mutations in CACNA1A result in great clinical heterogeneity with progressive symptoms, paroxysmal events or both. During infancy, clinical and neuroimaging findings may be unspecific, and no dysmorphic features have been reported. We present the clinical, radiological and evolutionary features of three patients with congenital ataxia, one of them carrying a new variant. We report the structural localization of variants and their expected functional consequences. There was an improvement in cerebellar syndrome over time despite a cerebellar atrophy progression, inconsistent response to acetazolamide and positive response to methylphenidate. The patients shared distinctive facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures and narrow nasal bridge. The two α1A affected residues are fully conserved throughout evolution and among the whole human CaV channel family. They contribute to the channel pore and the voltage sensor segment. According to structural data analysis and available functional characterization, they are expected to exert gain- (F1394L) and loss-of-function (R1664Q/R1669Q) effect, respectively. Among the CACNA1A-related phenotypes, our results suggest that non-progressive congenital ataxia is associated with developmental delay and dysmorphic features, constituting a recognizable syndromic neurodevelopmental disorder.
• dc.description.sponsorship This work was funded by the Spanish Ministry of Health, Consumer Affairs and Social Welfare, 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 FEDER (European Regional Development Fund).
• dc.format.mimetype application/pdf
• dc.identifier.citation Martínez-Monseny AF, Edo A, Casas-Alba D, Izquierdo-Serra M, Bolasell M, Conejo D, Martorell L, Muchart J, Carrera L, Ortez CI, Nascimento A, Oliva B, Fernández-Fernández JM, Serrano M. CACNA1A mutations causing early onset ataxia: profiling clinical, dysmorphic and structural-functional findings. Int J Mol Sci. 2021;22(10):5180. DOI: 10.3390/ijms22105180
• dc.identifier.doi http://dx.doi.org/10.3390/ijms22105180
• dc.identifier.issn 1422-0067
• dc.identifier.uri http://hdl.handle.net/10230/47763
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Int J Mol Sci. 2021;22(10):5180
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094809-B-I00
• dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword CACNA1A gene
• dc.subject.keyword CaV2.1 (P/Q-type) voltage-dependent calcium channel
• dc.subject.keyword Ataxia
• dc.subject.keyword Cerebellar atrophy
• dc.subject.keyword Dysmorphic traits
• dc.subject.keyword Early-onset cerebellar ataxia
• dc.title CACNA1A mutations causing early onset ataxia: profiling clinical, dysmorphic and structural-functional findings
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion