Pediatric dilated cardiomyopathy-associated LRRC10 (Leucine-Rich Repeat-Containing 10) variant reveals LRRC10 as an auxiliary subunit of cardiac L-Type Ca2+ channels

Marites T. Woon, Pamela A. Long, Louise Reilly, Jared M. Evans, Alexis M. Keefe, Martin R. Lea, Carl J. Beglinger, Ravi C. Balijepalli, Youngsook Lee, Timothy Mark Olson, Timothy J. Kamp

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (Cav1.2, β2CN2, and α2δ 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 Cav1.2. LRRC10 coexpression with Cav1.2 in the absence of auxiliary β2CN2 and α2δ subunits revealed coassociation of Cav1.2 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 Cav1.2 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.

Original languageEnglish (US)
Article numbere006428
JournalJournal of the American Heart Association
Volume7
Issue number3
DOIs
StatePublished - Feb 1 2018

Fingerprint

Dilated Cardiomyopathy
Leucine
Pediatrics
Exome
HEK293 Cells
Muscle Cells
Parents

Keywords

  • Cardiomyopathy
  • Genetics
  • Ion channel
  • Pediatrics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Pediatric dilated cardiomyopathy-associated LRRC10 (Leucine-Rich Repeat-Containing 10) variant reveals LRRC10 as an auxiliary subunit of cardiac L-Type Ca2+ channels. / 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 Mark; Kamp, Timothy J.

In: Journal of the American Heart Association, Vol. 7, No. 3, e006428, 01.02.2018.

Research output: Contribution to journalArticle

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 Mark ; Kamp, Timothy J. / Pediatric dilated cardiomyopathy-associated LRRC10 (Leucine-Rich Repeat-Containing 10) variant reveals LRRC10 as an auxiliary subunit of cardiac L-Type Ca2+ channels. In: Journal of the American Heart Association. 2018 ; Vol. 7, No. 3.
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title = "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 (Cav1.2, β2CN2, and α2δ 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 Cav1.2. LRRC10 coexpression with Cav1.2 in the absence of auxiliary β2CN2 and α2δ subunits revealed coassociation of Cav1.2 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 Cav1.2 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.",
keywords = "Cardiomyopathy, Genetics, Ion channel, Pediatrics",
author = "Woon, {Marites T.} and Long, {Pamela A.} and Louise Reilly and Evans, {Jared M.} and Keefe, {Alexis M.} and Lea, {Martin R.} and Beglinger, {Carl J.} and Balijepalli, {Ravi C.} and Youngsook Lee and Olson, {Timothy Mark} and Kamp, {Timothy J.}",
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T1 - Pediatric dilated cardiomyopathy-associated LRRC10 (Leucine-Rich Repeat-Containing 10) variant reveals LRRC10 as an auxiliary subunit of cardiac L-Type Ca2+ channels

AU - Woon, Marites T.

AU - Long, Pamela A.

AU - Reilly, Louise

AU - Evans, Jared M.

AU - Keefe, Alexis M.

AU - Lea, Martin R.

AU - Beglinger, Carl J.

AU - Balijepalli, Ravi C.

AU - Lee, Youngsook

AU - Olson, Timothy Mark

AU - Kamp, Timothy J.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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 (Cav1.2, β2CN2, and α2δ 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 Cav1.2. LRRC10 coexpression with Cav1.2 in the absence of auxiliary β2CN2 and α2δ subunits revealed coassociation of Cav1.2 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 Cav1.2 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.

AB - 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 (Cav1.2, β2CN2, and α2δ 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 Cav1.2. LRRC10 coexpression with Cav1.2 in the absence of auxiliary β2CN2 and α2δ subunits revealed coassociation of Cav1.2 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 Cav1.2 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.

KW - Cardiomyopathy

KW - Genetics

KW - Ion channel

KW - Pediatrics

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DO - 10.1161/JAHA.117.006428

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