CACNA1A mutations causing early onset ataxia: profiling clinical, dysmorphic and structural-functional findings
| Autor: | L. Carrera, Jordi Muchart, José M. Fernández-Fernández, Mercè Izquierdo-Serra, Loreto Martorell, Mercedes Serrano, Dídac Casas-Alba, Carlos Ortez, Mercè Bolasell, Andrés Nascimento, David Conejo, Antonio Martinez-Monseny, Albert Edo, Baldo Oliva |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
CaV2.1 (P/Q-type) voltage-dependent calcium channel Ataxia Prominent forehead Nasal bridge QH301-705.5 Catalysis Article Inorganic Chemistry Malalties del sistema nerviós Neurologia 03 medical and health sciences 0302 clinical medicine Neurodevelopmental disorder Neuroimaging medicine Biology (General) Physical and Theoretical Chemistry Hypertelorism QD1-999 Molecular Biology Spectroscopy business.industry Organic Chemistry CACNA1A gene Nervous system Diseases General Medicine medicine.disease Phenotype Computer Science Applications Chemistry 030104 developmental biology Neurology Cerebellar atrophy Dysmorphic traits medicine.symptom business Neuroscience 030217 neurology & neurosurgery Early-onset cerebellar ataxia |
| Zdroj: | International Journal of Molecular Sciences Dipòsit Digital de la UB Universidad de Barcelona Volume 22 Issue 10 International Journal of Molecular Sciences, Vol 22, Iss 5180, p 5180 (2021) |
| Popis: | 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. 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). |
| Databáze: | OpenAIRE |
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