Muscle dysfunction caused by loss ofMagel2in a mouse model of Prader-Willi and Schaaf-Yang syndromes

Abstract

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-Willi syndrome phenotypes. Gene-targeted mice lacking Magel2 have excess fat and decreased muscle, recapitulating altered body composition in Prader-Willi syndrome. We now demonstrate that Magel2 is expressed in the developing musculoskeletal system, and that loss of Magel2 causes muscle-related phenotypes in mice consistent with atrophy caused by altered autophagy. Magel2-null mice serve as a preclinical model for therapies targeting muscle structure and function in children lacking MAGEL2 diagnosed with Prader-Willi or Schaaf-Yang syndrome.

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome

“…Scoliosis data for individuals with PWS are wide-ranging, showing a prevalence of 40%–80%, and varying in age of onset and severity 5 38. It has been hypothesised through the use of Magel2 KO mice that MAGEL2 could be the scoliosis-determining gene in PWS 39. In our study, 33% of patients with SYS showed significant scoliosis of >10°, with curvatures of 16°, 52° and 65°.…”

Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty

“…The reduction in these ambulatory movements may suggest a reduction in anxiety, hypoactivity or a lack of interest toward the novel environment over time. Most recently, this Magel2 knockout mouse was shown to have poor muscle tone due aberrancies in muscle autophagy (Kamaludin et al 2016). This finding may account for some of the observed hypoactivity.…”

Cellular and disease functions of the Prader–Willi Syndrome geneMAGEL2

“…However, despite compromised hypothalamic circuits, mice do not develop hyperphagia or severe obesity, but they do display changes in body composition, such as decreased lean mass and increased adiposity distribution of muscle fiber types and bone mineral content (114, 122-125). This suggests that MAGEL2-dependent pathways may contribute to hypotonia, altered body composition and a high incidence of musculoskeletal abnormalities in PWS and SHFYNG (97, 126-129).…”