Pediatric Dilated Cardiomyopathy-Associated (Leucine-Rich Repeat-Containing 10) Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L-Type Ca 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 have been suggested to cause DCM, and deletion of 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 , I195T. Coexpression of I195T with the L-type Ca channel (Ca1.2, β, and αδ subunits) in HEK293 cells resulted in a significant ≈0.5-fold decrease in I at 0 mV, in contrast to the ≈1.4-fold increase in I by coexpression of (n=9-12, <0.05). Coexpression of or I195T did not alter the surface membrane expression of Ca1.2. coexpression with Ca1.2 in the absence of auxiliary β and αδ subunits revealed coassociation of Ca1.2 and LRRC10 and a hyperpolarizing shift in the voltage dependence of activation (n=6-9, <0.05). Ventricular myocytes from mice had significantly smaller I, and coimmunoprecipitation experiments confirmed association between LRRC10 and the Ca1.2 subunit in mouse hearts.

CONCLUSIONS

Examination of a patient with DCM revealed homozygosity for a previously unreported variant: I195T. Wild-type and I195T LRRC10 function as cardiac-specific subunits of L-type Ca channels and exert dramatically different effects on channel gating, providing a potential link to DCM.