Pediatric Dilated Cardiomyopathy‐Associated LRRC10 (Leucine‐Rich Repeat–Containing 10) Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L‐Type Ca2+ Channels

BackgroundGenetic 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 ResultsWhole‐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 Ca2+ channel (Cav1.2, β2CN2, and α2δ subunits) in HEK293 cells resulted in a significant ≈0.5‐fold decrease in ICa,L at 0 mV, in contrast to the ≈1.4‐fold increase in ICa,L by coexpression of LRRC10 (n=9–12, P<0.05). Coexpression of LRRC10 or I195T LRRC10 did not alter the surface membrane expression of Cav1.2. LRRC10 coexpression with Cav1.2 in the absence...