Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Marshall W. Hogarth; Peter J. Houweling; Kristen C. Thomas; Heather Gordish-Dressman; Luca Bello; V. Vishwanathan; S. Chidambaranathan; W. Douglas Biggar; Laura C. McAdam; Jean K. Mah; Mar Tulinius; Avital Cnaan; Lauren P. Morgenroth; Robert Leshner; Carolina Tesi-Rocha; Mathula Thangarajh; Tina Duong; Andrew Kornberg; Monique Ryan; Yoram Nevo; Alberto Dubrovsky; Paula R. Clemens; Hoda Abdel-Hamid; Anne M. Connolly; Alan Pestronk; Jean Teasley; Tulio E. Bertorini; Richard Webster; Hanna Kolski; Nancy Kuntz; Sherilyn Driscoll; John B. Bodensteiner; Jose Carlo; Ksenija Gorni; Timothy Lotze; John W. Day; Peter Karachunski; Erik K. Henricson; Richard T. Abresch; Craig M. McDonald; Elena Pegoraro; Eric P. Hoffman; Stewart I. Head; Kathryn N. North

doi:10.1038/ncomms14143

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Marshall W. Hogarth
, Peter J. Houweling
, Kristen C. Thomas
, Heather Gordish-Dressman
, Luca Bello
, V. Vishwanathan
, S. Chidambaranathan
, W. Douglas Biggar
, Laura C. McAdam
, Jean K. Mah
, Mar Tulinius
, Avital Cnaan
, Lauren P. Morgenroth
, Robert Leshner
, Carolina Tesi-Rocha
, Mathula Thangarajh
, Tina Duong
, Andrew Kornberg
, Monique Ryan
, Yoram Nevo

Alberto Dubrovsky, Paula R. Clemens, Hoda Abdel-Hamid, Anne M. Connolly, Alan Pestronk, Jean Teasley, Tulio E. Bertorini, Richard Webster, Hanna Kolski, Nancy Kuntz, Sherilyn Driscoll, John B. Bodensteiner, Jose Carlo, Ksenija Gorni, Timothy Lotze, John W. Day, Peter Karachunski, Erik K. Henricson, Richard T. Abresch, Craig M. McDonald, Elena Pegoraro, Eric P. Hoffman, Stewart I. Head, Kathryn N. North

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

Abstract

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that Î±-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that Î±-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.

Original language	English
Article number	14143
Number of pages	13
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14143
Publication status	Published - 2017

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Keywords

gene expression
genotype
metabolism

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10.1038/ncomms14143

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Hogarth, M. W., Houweling, P. J., Thomas, K. C., Gordish-Dressman, H., Bello, L., Vishwanathan, V., Chidambaranathan, S., Biggar, W. D., McAdam, L. C., Mah, J. K., Tulinius, M., Cnaan, A., Morgenroth, L. P., Leshner, R., Tesi-Rocha, C., Thangarajh, M., Duong, T., Kornberg, A., Ryan, M., ... North, K. N. (2017). Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy. Nature Communications, 8, Article 14143. https://doi.org/10.1038/ncomms14143

@article{f9854f961ac6497280995bbef0b65b7b,

title = "Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy",

abstract = "Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that {\^I}±-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that {\^I}±-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.",

keywords = "gene expression, genotype, metabolism",

author = "Hogarth, \{Marshall W.\} and Houweling, \{Peter J.\} and Thomas, \{Kristen C.\} and Heather Gordish-Dressman and Luca Bello and V. Vishwanathan and S. Chidambaranathan and Biggar, \{W. Douglas\} and McAdam, \{Laura C.\} and Mah, \{Jean K.\} and Mar Tulinius and Avital Cnaan and Morgenroth, \{Lauren P.\} and Robert Leshner and Carolina Tesi-Rocha and Mathula Thangarajh and Tina Duong and Andrew Kornberg and Monique Ryan and Yoram Nevo and Alberto Dubrovsky and Clemens, \{Paula R.\} and Hoda Abdel-Hamid and Connolly, \{Anne M.\} and Alan Pestronk and Jean Teasley and Bertorini, \{Tulio E.\} and Richard Webster and Hanna Kolski and Nancy Kuntz and Sherilyn Driscoll and Bodensteiner, \{John B.\} and Jose Carlo and Ksenija Gorni and Timothy Lotze and Day, \{John W.\} and Peter Karachunski and Henricson, \{Erik K.\} and Abresch, \{Richard T.\} and McDonald, \{Craig M.\} and Elena Pegoraro and Hoffman, \{Eric P.\} and Head, \{Stewart I.\} and North, \{Kathryn N.\}",

year = "2017",

doi = "10.1038/ncomms14143",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Hogarth, MW, Houweling, PJ, Thomas, KC, Gordish-Dressman, H, Bello, L, Vishwanathan, V, Chidambaranathan, S, Biggar, WD, McAdam, LC, Mah, JK, Tulinius, M, Cnaan, A, Morgenroth, LP, Leshner, R, Tesi-Rocha, C, Thangarajh, M, Duong, T, Kornberg, A, Ryan, M, Nevo, Y, Dubrovsky, A, Clemens, PR, Abdel-Hamid, H, Connolly, AM, Pestronk, A, Teasley, J, Bertorini, TE, Webster, R, Kolski, H, Kuntz, N, Driscoll, S, Bodensteiner, JB, Carlo, J, Gorni, K, Lotze, T, Day, JW, Karachunski, P, Henricson, EK, Abresch, RT, McDonald, CM, Pegoraro, E, Hoffman, EP, Head, SI & North, KN 2017, 'Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy', Nature Communications, vol. 8, 14143. https://doi.org/10.1038/ncomms14143

TY - JOUR

T1 - Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

AU - Hogarth, Marshall W.

AU - Houweling, Peter J.

AU - Thomas, Kristen C.

AU - Gordish-Dressman, Heather

AU - Bello, Luca

AU - Vishwanathan, V.

AU - Chidambaranathan, S.

AU - Biggar, W. Douglas

AU - McAdam, Laura C.

AU - Mah, Jean K.

AU - Tulinius, Mar

AU - Cnaan, Avital

AU - Morgenroth, Lauren P.

AU - Leshner, Robert

AU - Tesi-Rocha, Carolina

AU - Thangarajh, Mathula

AU - Duong, Tina

AU - Kornberg, Andrew

AU - Ryan, Monique

AU - Nevo, Yoram

AU - Dubrovsky, Alberto

AU - Clemens, Paula R.

AU - Abdel-Hamid, Hoda

AU - Connolly, Anne M.

AU - Pestronk, Alan

AU - Teasley, Jean

AU - Bertorini, Tulio E.

AU - Webster, Richard

AU - Kolski, Hanna

AU - Kuntz, Nancy

AU - Driscoll, Sherilyn

AU - Bodensteiner, John B.

AU - Carlo, Jose

AU - Gorni, Ksenija

AU - Lotze, Timothy

AU - Day, John W.

AU - Karachunski, Peter

AU - Henricson, Erik K.

AU - Abresch, Richard T.

AU - McDonald, Craig M.

AU - Pegoraro, Elena

AU - Hoffman, Eric P.

AU - Head, Stewart I.

AU - North, Kathryn N.

PY - 2017

Y1 - 2017

N2 - Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that Î±-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that Î±-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.

AB - Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that Î±-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that Î±-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.

KW - gene expression

KW - genotype

KW - metabolism

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:42414

U2 - 10.1038/ncomms14143

DO - 10.1038/ncomms14143

M3 - Article

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14143

ER -

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Abstract

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