Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2

Mantuano, Elide; Romano, Silvia; Veneziano, Liana; Gellera, Cinzia; Castellotti, Barbara; Caimi, Sara; Testa, D.; Estienne, Margherita; Zorzi, Giovanna; Bugiani, Marianna; Rajabally, Yusuf A.; Barcina, M.J. García; Servidei, Serenella; Panico, Aurora; Frontali, Marina; Mariotti, Caterina

doi:10.1016/j.jns.2010.01.010

Cited by 63 publications

(69 citation statements)

References 32 publications

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“…5 The most common form of episodic ataxia is EA2, caused by a variety of point mutations in the same calcium channel gene (CACNA1A) associated with SCA6 and familial hemiplegic migraine. 12 Genetics. The ADCAs for which specific genetic information is available are summarized in Table 1.…”

Section: Types Of Hereditary Ataxiamentioning

confidence: 99%

Hereditary ataxias: overview

Jayadev

Bird

2013

Genetics in Medicine

216

165

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Section: Types Of Hereditary Ataxiamentioning

confidence: 99%

Hereditary ataxias: overview

Jayadev

Bird

2013

Genetics in Medicine

216

165

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“…[1][2][3] These conditions occasionally overlap since patients with FHM1 may have cerebellar symptoms, and 33% of patients with SCA6 display episodic features characteristic of EA2. [4][5][6] EA2 usually presents during childhood or early adulthood 7 with intermittent episodes of ataxia and nystagmus lasting minutes to days. 8 These episodes are classically triggered by exertion, stress, heat, fever, alcohol, caffeine or drugs such as phenytoin.…”

Section: Introductionmentioning

confidence: 99%

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

et al. 2015

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CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of Ca V 2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

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“…For this reason, a haploinsufficiency mechanism could be supposed in EA2 patients carrying CACNA1A mutations leading to PTCs (that account for N60% of the total mutations), especially with early stop codon like those recently described in the first protein domain [10]. These latter cases are particularly significant because the truncating mutations involve the protein N-terminus, where the dominant negative effect over the wild type protein was shown [35].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations of the CACNA1A gene leading to a complete or a partial impairment of Ca 2+ influx [4][5][6][7][8] are responsible for Episodic Ataxia type 2 (EA2, OMIM 108500). EA2 is an early onset, autosomal dominant disorder characterised by attacks of vertigo/ataxia, visual disturbance, dysarthria, interictal cerebellar deficit of extremely variable severity, and cerebellar atrophy; epilepsy has occasionally been described [9,10]. A dominant negative effect of the Ca V 2.1 mutated protein affecting the wild type product, rather than a haploinsufficiency, has been hypothesised [6,[11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…The hypothesis that cacna1a mutations leading to PTC are subject to NMD also has implications for human EA2 mutations of the same kind, accounting for more than 60% of the total [10]. If mRNA turns out to be degraded, no truncated protein will be present, thus indicating a haploinsufficiency mechanism rather than a dominant negative effect.…”

Section: Introductionmentioning

confidence: 99%

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Dramatically different levels of cacna1a gene expression between pre-weaning wild type and leaner mice

Veneziano¹,

Albertosi²,

Pesci³

et al. 2011

Journal of the Neurological Sciences

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Loss of function mutations of the CACNA1A gene, coding for the α1A subunit of P/Q type voltage-gated calcium channel (Ca V 2.1), are responsible for Episodic Ataxia type 2 (EA2), an autosomal dominant disorder. A dominant negative effect of the EA2 mutated protein, rather than a haploinsufficiency mechanism, has been hypothesised both for protein-truncating and missense mutations. We analysed the cacna1a mRNA expression in leaner mice carrying a cacna1a mutation leading to a premature stop codon. The results showed a very low mutant mRNA expression compared to the wild type allele. Although the mutant mRNA slightly increases with age, its low level is likely due to degradation by nonsense mediated decay, a quality control mechanism that selectively degrades mRNA harbouring premature stop codons. These data have implications for EA2 in humans, suggesting a haploinsufficiency mechanism at least for some of the CACNA1A mutations leading to a premature stop codon.

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Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2

Cited by 63 publications

References 32 publications

Hereditary ataxias: overview

Hereditary ataxias: overview

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

Dramatically different levels of cacna1a gene expression between pre-weaning wild type and leaner mice

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