Pediatric Dilated Cardiomyopathy‐Associated LRRC10 (Leucine‐Rich Repeat–Containing 10) Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L‐Type Ca2+ Channels. Issue 3 (3rd February 2018)

• Record Type: Journal Article
• Authors: Woon, Marites T.; Long, Pamela A.; Reilly, Louise; Evans, Jared M.; Keefe, Alexis M.; Lea, Martin R.; Beglinger, Carl J.; Balijepalli, Ravi C.; Lee, Youngsook; Olson, Timothy M.; Kamp, Timothy J.
• Is Part Of: Journal of the American Heart Association. Volume 7:Issue 3(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-02-03
• Subjects: cardiomyopathy -- genetics -- ion channel -- pediatrics; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.117.006428
• Languages: English
• ISSNs: 2047-9980

Abstract

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 Ca 2+ channel (Cav 1.2, β2CN2, and α2 δ 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 Cav 1.2. LRRC10 coexpression with Cav 1.2 in the absence of auxiliary β2CN2 and α2 δ subunits revealed coassociation of Cav 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 ICa, L, and coimmunoprecipitation experiments confirmed association between LRRC10 and the Cav 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.