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

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(v)1.2, beta(2CN2), and alpha(2)delta subunits) in HEK293 cells resulted in a significant approximate to 0.5-fold decrease in I-Ca,I-L at 0 mV, in contrast to the approximate to 1.4-fold increase in I-Ca,I-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 beta(2CN2) and alpha(2)delta 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,I-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. Wildtype 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.