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Int J Obes (Lond). 2017 Jul;41(7):1154-1157. doi: 10.1038/ijo.2017.72. Epub 2017 Mar 15.

Exploring the relationship between α-actinin-3 deficiency and obesity in mice and humans.

Houweling PJ1,2,3, Berman YD1,4,5, Turner N6,7, Quinlan KGR1,6, Seto JT2,3, Yang N1, Lek M1,4,8,9, Macarthur DG1,8,9, Cooney G7,10, North KN1,2,3.

Author information

Institute for Neuroscience and Muscle Research (INMR), The Children's Hospital at Westmead, NSW, Australia.
Department of Pediatrics, The University of Melbourne, Victoria, Australia.
Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
Discipline of Child and Adolescent Health, Sydney Medical School, The University of Sydney, New South Wales, Australia.
Department of Clinical Genetics, Royal North Shore Hospital, New South Wales, Australia.
Faculty of Science, School of Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, New South Wales, Australia.
Diabetes and Metabolism Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Charles Perkins Centre, Sydney Medical School, The University of Sydney, New South Wales, Australia.


Obesity is a worldwide health crisis, and the identification of genetic modifiers of weight gain is crucial in understanding this complex disorder. A common null polymorphism in the fast fiber-specific gene ACTN3 (R577X) is known to influence skeletal muscle function and metabolism. α-Actinin-3 deficiency occurs in an estimated 1.5 billion people worldwide, and results in reduced muscle strength and a shift towards a more efficient oxidative metabolism. The X-allele has undergone strong positive selection during recent human evolution, and in this study, we sought to determine whether ACTN3 genotype influences weight gain and obesity in mice and humans. An Actn3 KO mouse has been generated on two genetic backgrounds (129X1/SvJ and C57BL/6J) and fed a high-fat diet (HFD, 45% calories from fat). Anthropomorphic features (including body weight) were examined and show that Actn3 KO 129X1/SvJ mice gained less weight compared to WT. In addition, six independent human cohorts were genotyped for ACTN3 R577X (Rs1815739) and body mass index (BMI), waist-to-hip ratio-adjusted BMI (WHRadjBMI) and obesity-related traits were assessed. In humans, ACTN3 genotype alone does not contribute to alterations in BMI or obesity.

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