Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies.
Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing.
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Institut de Biomedicina de la Universitat de Barcelona (IBUB) Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain.
Oriel
O
Carreño
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain ; Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona Barcelona, Spain.
Roser
R
Corominas
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra Barcelona, Spain.
Selma Angèlica
SA
Serra
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Institut de Biomedicina de la Universitat de Barcelona (IBUB) Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain.
Cèlia
C
Sintas
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Institut de Biomedicina de la Universitat de Barcelona (IBUB) Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain.
Noèlia
N
Fernández-Castillo
Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona Barcelona, Spain.
Marta
M
Vila-Pueyo
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Institut de Biomedicina de la Universitat de Barcelona (IBUB) Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain.
Claudio
C
Toma
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra Barcelona, Spain.
Gemma G
GG
Gené
First Department of Pediatrics, Agia Sofia Hospital, University of Athens Athens, Greece.
Roser
R
Pons
Sección de Neurología, Complejo Hospitalario Arquitecto Marcide-Novoa Santos Ferrol, Spain.
Miguel
M
Llaneza
Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain ; Fundación Pública Galega de Medicina Xenómica Santiago de Compostela, Spain.
María-Jesús
MJ
Sobrido
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Institut de Biomedicina de la Universitat de Barcelona (IBUB) Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain.
Daniel
D
Grinberg
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra Barcelona, Spain.
Miguel Ángel
MÁ
Valverde
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra Barcelona, Spain.
José Manuel
JM
Fernández-Fernández
Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona Barcelona, Spain.
Alfons
A
Macaya
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain ; Institut de Biomedicina de la Universitat de Barcelona (IBUB) Barcelona, Spain ; Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III Spain.
Bru
B
Cormand
ATP1A2; CACNA1A; functional studies; hemiplegic migraine; mutation analysis