Pinggera, Alexandra, Mackenroth, Luisa, Rump, Andreas, Schallner, Jens, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Wollnik, Bernd and Striessnig, Joerg ORCID: 0000-0002-9406-7120 (2017). New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Hum. Mol. Genet., 26 (15). S. 2923 - 2933. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

Full text not available from this repository.

Abstract

CACNA1D encodes the pore-forming alpha 1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Cav1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarily focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy. For the functional characterization we introduced mutation V401L into two major C-terminal long and short Cav1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings. Mutation V401L, localized within the channel's activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Cav1.3 splice variants. Altogether, these gating changes are expected to result in enhanced Ca2+-influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+-channel blocker isradipine. Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures and neurological abnormalities) caused by similar Cav1.3 gain-of-function mutations.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pinggera, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackenroth, LuisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rump, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schallner, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striessnig, JoergUNSPECIFIEDorcid.org/0000-0002-9406-7120UNSPECIFIED
URN: urn:nbn:de:hbz:38-224074
DOI: 10.1093/hmg/ddx175
Journal or Publication Title: Hum. Mol. Genet.
Volume: 26
Number: 15
Page Range: S. 2923 - 2933
Date: 2017
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; CA2+ CHANNELS; CA(V)1.3 CHANNELS; CALCIUM-CHANNELS; BASOLATERAL AMYGDALA; CHROMAFFIN CELLS; DOMAIN; INACTIVATION; MODULATION; MECHANISMSMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22407

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item