Journal ArticleDOI
Rare CACNA1A mutations leading to congenital ataxia.
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TLDR
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 are dealt with.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.read more
Citations
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Journal ArticleDOI
Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol))
Journal Article
Late onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A
TD Graves,Paola Imbrici,L. H. Eunson,Kailash P. Bhatia,NH Wodia,Michael G. Hanna,Dimitri M. Kullmann +6 more
TL;DR: In this paper, a case of late-onset ataxia type 2 was associated with the first multiple base pair insertion in CACNA1A, suggesting that genetically induced reduction in calcium channel function may associate with cases of lateonset EA2.
Journal ArticleDOI
Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies
TL;DR: In this article, a review summarizes the current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels, with a special focus on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts.
Journal ArticleDOI
Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?
TL;DR: In this paper, a comprehensive review of the ion channel genes encoding K+, Ca2+, Na+, and Cl- channels was presented, which indicated that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain.
Journal ArticleDOI
Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2.
Ana Arteche-López,Maria Isabel Alvarez-Mora,M T Sánchez Calvin,J M Lezana Rosales,C Palma Milla,M J Gómez Rodríguez,I Gomez Manjón,Alberto Blázquez,A Juarez Rufián,P Ramos Gómez,O Sierra Tomillo,I Hidalgo Mayoral,R Pérez de la Fuente,I J Posada Rodríguez,L I González Granado,Miguel A. Martín,Juan Francisco Quesada-Espinosa,M. Moreno-García +17 more
TL;DR: The first patients harboring homozygous disease-related variants in three genes were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively as discussed by the authors.
References
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Journal ArticleDOI
Expansion of the phenotypic spectrum of the CACNA1A T666M mutation: a family with familial hemiplegic migraine type 1, cerebellar atrophy and mental retardation.
TL;DR: Clinical, neuropsychological and genetic data are presented of a large German FHM1 family with the previously reported T666M CACNA1A mutation, in which several individuals suffered from early-onset permanent MR in addition to typical attacks of FHM, suggesting that MR can be part of the phenotypic spectrum not only of F HM2, but also of Fhm1.
Journal ArticleDOI
CACNA1A mutation in a EA-2 patient responsive to acetazolamide and valproic acid.
TL;DR: This study identified a new missense mutation in exon 12 of the CACNA1A gene from a patient with EA-2 whose symptoms could be controlled with a combination of acetazolamide and valproic acid.
Journal ArticleDOI
A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis
Selma A. Serra,Ester Cuenca-León,Artur Llobet,Francisca Rubio-Moscardo,Cristina Plata,Oriel Carreño,Noèlia Fernàndez-Castillo,Roser Corominas,Miguel A. Valverde,Alfons Macaya,Bru Cormand,José M. Fernández-Fernández +11 more
TL;DR: The findings reveal the importance of I-II loop structural integrity in the functional interaction between P/Q channel and proteins of the vesicle-docking/fusion machinery, and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype.
Journal ArticleDOI
S1 Constrains S4 in the Voltage Sensor Domain of Kv7.1 K+ Channels
Yoni Haitin,Ilanit Yisharel,Eti Malka,Liora Shamgar,Hella Schottelndreier,Asher Peretz,Yoav Paas,Bernard Attali +7 more
TL;DR: In this article, the S4 helix is known to couple to channel gate opening and closing, but the nature of S4 motion is unclear, and the role of the S1 segment in steering S4 motions during Kv7.1 gating is investigated.
Journal ArticleDOI
Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop.
Federica Cricchi,C. Di Lorenzo,G. S. Grieco,C. Rengo,Alessio Cardinale,M. Racaniello,Filippo M. Santorelli,G. Nappi,Francesco Pierelli,Carlo Casali +9 more
TL;DR: Two sisters with a heterogeneous clinical phenotype with reported episodes of vertigo, headache and gait imbalance since late childhood, with good response to acetazolamide, before developing moderate chronic cerebellar ataxia are reported on.
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