title: CACNA1H mutations in autism spectrum disorders.
abstract: Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by impaired social interaction, communication skills, and restricted and repetitive behavior. The genetic causes for autism are largely unknown. Previous studies implicate CACNA1C (L-type Ca(V)1.2) calcium channel mutations in a disorder associated with autism (Timothy syndrome). Here, we identify missense mutations in the calcium channel gene CACNA1H (T-type Ca(V)3.2) in 6 of 461 individuals with ASD. These mutations are located in conserved and functionally relevant domains and are absent in 480 ethnically matched controls (p = 0.014, Fisher's exact test). Non-segregation within the pedigrees between the mutations and the ASD phenotype clearly suggest that the mutations alone are not responsible for the condition. However, functional analysis shows that all these mutations significantly reduce Ca(V)3.2 channel activity and thus could affect neuronal function and potentially brain development. We conclude that the identified mutations could contribute to the development of the ASD phenotype.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Igor
authors.initials: I
authors.lastname: Splawski
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Yoo
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; Neurobiology, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: scstotz@enders.tch.harvard.edu.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Stotz
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Allison
authors.initials: A
authors.lastname: Cherry
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Keating
mesh_terms: D001321:Autistic Disorder / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005192:Family Health; D006801:Humans; D007700:Kinetics; D017720:Molecular Epidemiology; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type