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J. Biol. Chem., Vol. 281, Issue 31, 22085-22091, August 4, 2006

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CACNA1H Mutations in Autism Spectrum Disorders^*

Igor Splawski¹, Dana S. Yoo¹, Stephanie C. Stotz^¶12, Allison Cherry, David E. Clapham^¶, and Mark T. Keating

From the Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Departments of Pediatrics, Cell Biology, and ^¶Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

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_V1.2) 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_V3.2) 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_V3.2 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.

Received for publication, April 6, 2006 , and in revised form, May 31, 2006.

^* This work was supported by grants from the Charles H. Hood Foundation (to I. S.), the Alberta Heritage Foundation for Medical Research (to S. C. S), and the Canadian Institutes of Health Research (S.C.S) and by National Institutes of Health Grants T32 HL07572 (to I. S.), HL46401 and HL52338 (to M. T. K.), and P30 HD18655 (to the Mental Retardation Research Center at Children's Hospital). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Table 1.

¹ These authors contributed equally to the work.

² To whom correspondence should be addressed: Children's Hospital Boston, Enders 1314, 320 Longwood Ave., Boston, MA 02115. E-mail: scstotz{at}enders.tch.harvard.edu.

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