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Pediatric Dilated Cardiomyopathy‐Associated LRRC10 (Leucine‐Rich Repeat–Containing 10) Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L‐Type Ca2+ Channels
- Source :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
- Publication Year :
- 2018
- Publisher :
- John Wiley and Sons Inc., 2018.
-
Abstract
- Background Genetic causes of dilated cardiomyopathy (DCM) are incompletely understood. LRRC10 (leucine‐rich repeat–containing 10) is a cardiac‐specific protein of unknown function. Heterozygous mutations in LRRC10 have been suggested to cause DCM, and deletion of Lrrc10 in mice results in DCM. Methods and Results Whole‐exome sequencing was carried out on a patient who presented at 6 weeks of age with DCM and her unaffected parents, filtering for rare, deleterious, recessive, and de novo variants. Whole‐exome sequencing followed by trio‐based filtering identified a homozygous recessive variant in LRRC10 , I195T. Coexpression of I195T LRRC10 with the L‐type Ca 2+ channel (Ca v 1.2, β 2CN2 , and α 2 δ subunits) in HEK293 cells resulted in a significant ≈0.5‐fold decrease in I Ca,L at 0 mV, in contrast to the ≈1.4‐fold increase in I Ca,L by coexpression of LRRC10 (n=9–12, P LRRC10 or I195T LRRC10 did not alter the surface membrane expression of Ca v 1.2. LRRC10 coexpression with Ca v 1.2 in the absence of auxiliary β 2CN2 and α 2 δ subunits revealed coassociation of Ca v 1.2 and LRRC10 and a hyperpolarizing shift in the voltage dependence of activation (n=6–9, P Lrrc10 −/− mice had significantly smaller I Ca,L , and coimmunoprecipitation experiments confirmed association between LRRC10 and the Ca v 1.2 subunit in mouse hearts. Conclusions Examination of a patient with DCM revealed homozygosity for a previously unreported LRRC10 variant: I195T. Wild‐type and I195T LRRC10 function as cardiac‐specific subunits of L‐type Ca 2+ channels and exert dramatically different effects on channel gating, providing a potential link to DCM.
- Subjects :
- 0301 basic medicine
Cardiomyopathy, Dilated
pediatrics
Calcium Channels, L-Type
Protein subunit
DNA Mutational Analysis
Cardiomyopathy
Muscle Proteins
Leucine-rich repeat
Membrane Potentials
03 medical and health sciences
Exome Sequencing
Genetics
Medicine
Animals
Humans
Genetic Predisposition to Disease
Myocytes, Cardiac
Calcium Signaling
Ion channel
Original Research
Mice, Knockout
business.industry
Homozygote
Microfilament Proteins
Infant
Dilated cardiomyopathy
L type ca2 channels
Ion Channels/Membrane Transport
medicine.disease
Molecular biology
Electrophysiology
Mice, Inbred C57BL
030104 developmental biology
HEK293 Cells
Phenotype
ion channel
Mutation
cardiovascular system
Female
Cardiology and Cardiovascular Medicine
business
cardiomyopathy
Ion Channel Gating
Subjects
Details
- Language :
- English
- ISSN :
- 20479980
- Volume :
- 7
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
- Accession number :
- edsair.doi.dedup.....11a3a7afa7851146edd0acfa591b4dcd