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

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

  • Brain. 2018 Jul 1;141(7):1998-2013. doi: 10.1093/brain/awy145.
Jean Chemin 1 2,  Karine Siquier-Pernet 3 4,  Michaël Nicouleau 3 4,  Giulia Barcia 3 4,  Ali Ahmad 1 2,  Daniel Medina-Cano 3 4,  Sylvain Hanein 5,  Nami Altin 3 4,  Laurence Hubert 5,  Christine Bole-Feysot 6,  Cécile Fourage 7 8,  Patrick Nitschké 7,  Julien Thevenon 9,  Marlène Rio 4 8,  Pierre Blanc 4 8,  Céline Vidal 5,  Nadia Bahi-Buisson 3 10 11,  Isabelle Desguerre 3 11,  Arnold Munnich 3 8,  Stanislas Lyonnet 3 8 10,  Nathalie Boddaert 3 12 13,  Emily Fassi 14,  Marwan Shinawi 14,  Holly Zimmerman 15,  Jeanne Amiel 3 8 10,  Laurence Faivre 9,  Laurence Colleaux 3 4,  Philippe Lory 1 2,  Vincent Cantagrel 3 4
Affiliations

Affiliations

  • 1 IGF, CNRS, INSERM, University of Montpellier, Montpellier, France.
  • 2 LabEx 'Ion Channel Science and Therapeutics', Montpellier, France.
  • 3 Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
  • 4 Laboratory of developmental brain disorders, INSERM UMR, Paris, France.
  • 5 Translational Genetics, INSERM UMR, Imagine Institute, Paris, France.
  • 6 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Genomic Core Facility, Paris, France.
  • 7 Paris-Descartes Sorbonne Paris-Cité University, Imagine Institute, Bioinformatics Core Facility, Paris, France.
  • 8 Service de Génétique, Necker Enfants Malades University Hospital, APHP, Paris, France.
  • 9 Centre de Génétique et Centre de Référence "Anomalies du Développement et Syndromes Malformatifs", Hôpital d'Enfants, CHU Dijon, Dijon, France.
  • 10 Laboratory of embryology and genetics of congenital malformations, INSERM UMR1163, Paris, France.
  • 11 Service de neurologie pédiatrique, Necker Enfants Malades University Hospital, APHP, Paris, France.
  • 12 Pediatric Radiology Department, Necker Enfants Malades University Hospital, APHP, Paris, France.
  • 13 Image - Institut Imagine, INSERM UMR1163 and INSERM U1000, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, France.
  • 14 Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 15 Division of Genetics, Department of Pediatrics, University of Mississippi Medical Center, 2500N State St, Jackson, MS, USA.
PMID: 29878067 DOI: 10.1093/brain/awy145
Abstract

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 Cav3.1 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 (∼5 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 Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.

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