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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 <0.05). Coexpression of  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 <0.05). Ventricular myocytes from  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.

journal of the american heart association

Pediatric Dilated Cardiomyopathy‐Associated  LRRC10  (Leucine‐Rich Repeat–Containing 10) Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L‐Type Ca 2+  Channels