TY - JOUR
T1 - De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene
AU - Chemin, Jean
AU - Siquier-Pernet, Karine
AU - Nicouleau, Michaël
AU - Barcia, Giulia
AU - Ahmad, Ali
AU - Medina-Cano, Daniel
AU - Hanein, Sylvain
AU - Altin, Nami
AU - Hubert, Laurence
AU - Bole-Feysot, Christine
AU - Fourage, Cécile
AU - Nitschké, Patrick
AU - Thevenon, Julien
AU - Rio, Marlène
AU - Blanc, Pierre
AU - Vidal, Céline
AU - Bahi-Buisson, Nadia
AU - Desguerre, Isabelle
AU - Munnich, Arnold
AU - Lyonnet, Stanislas
AU - Boddaert, Nathalie
AU - Fassi, Emily
AU - Shinawi, Marwan
AU - Zimmerman, Holly
AU - Amiel, Jeanne
AU - Faivre, Laurence
AU - Colleaux, Laurence
AU - Lory, Philippe
AU - Cantagrel, Vincent
N1 - Publisher Copyright:
© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
KW - CACNA1G
KW - Ca v 3.1
KW - cerebellar atrophy
KW - de novo mutation
KW - voltage-gated calcium channel
UR - http://www.scopus.com/inward/record.url?scp=85050795161&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050795161&partnerID=8YFLogxK
U2 - 10.1093/brain/awy145
DO - 10.1093/brain/awy145
M3 - Article
C2 - 29878067
AN - SCOPUS:85050795161
SN - 0006-8950
VL - 141
SP - 1998
EP - 2013
JO - Brain
JF - Brain
IS - 7
ER -