Universität zu Köln

Breitenkamp, Alexandra F. S., Matthes, Jan ORCID: 0000-0003-2754-1555, Nass, Robert Daniel ORCID: 0000-0003-4446-8898, Sinzig, Judith ORCID: 0000-0002-3693-3318, Lehmkuhl, Gerd, Nuernberg, Peter and Herzig, Stefan (2014). Rare Mutations of CACNB2 Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function. PLoS One, 9 (4). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits Ca(V)1.2 (CACNA1C) and Ca-V beta 2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Breitenkamp, Alexandra F. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Matthes, Jan UNSPECIFIED orcid.org/0000-0003-2754-1555 UNSPECIFIED Nass, Robert Daniel UNSPECIFIED orcid.org/0000-0003-4446-8898 UNSPECIFIED Sinzig, Judith UNSPECIFIED orcid.org/0000-0002-3693-3318 UNSPECIFIED Lehmkuhl, Gerd UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Herzig, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-440544
DOI:	10.1371/journal.pone.0095579
Journal or Publication Title:	PLoS One
Volume:	9
Number:	4
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BETA-SUBUNITS; TIMOTHY-SYNDROME; CA2+ CHANNEL; EXPRESSION; GENETICS; INACTIVATION; HETEROGENEITY; LOCALIZATION; MODULATION; ARRHYTHMIA Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44054