De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Jean Chemin, Karine Siquier-Pernet, Michaël Nicouleau, Giulia Barcia, Ali Ahmad, Daniel Medina-Cano, Sylvain Hanein, Nami Altin, Laurence Hubert, Christine Bole-Feysot, Cécile Fourage, Patrick Nitschké, Julien Thevenon, Marlène Rio, Pierre Blanc, Céline Vidal, Nadia Bahi-Buisson, Isabelle Desguerre, Arnold Munnich, Stanislas LyonnetNathalie Boddaert, Emily Fassi, Marwan Shinawi, Holly Zimmerman, Jeanne Amiel, Laurence Faivre, Laurence Colleaux, Philippe Lory, Vincent Cantagrel

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Ca v 3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics ( 1/45 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Ca v 3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.

Original languageEnglish (US)
Pages (from-to)1998-2013
Number of pages16
Issue number7
StatePublished - Jul 1 2018
Externally publishedYes


  • Ca v 3.1
  • cerebellar atrophy
  • de novo mutation
  • voltage-gated calcium channel

ASJC Scopus subject areas

  • Clinical Neurology


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