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

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 Ca²⁺ channel (Ca_v1.2, β_2CN2, and α₂δ 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_v1.2. LRRC10 coexpression with Ca_v1.2 in the absence of auxiliary β_2CN2 and α₂δ subunits revealed coassociation of Ca_v1.2 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_v1.2 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 Ca²⁺ channels and exert dramatically different effects on channel gating, providing a potential link to DCM.

Keywords: cardiomyopathy; genetics; ion channel; pediatrics.