2. Academic Validation
  3. SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy

SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy

  • Am J Hum Genet. 2014 Aug 7;95(2):218-26. doi: 10.1016/j.ajhg.2014.07.004.
Pankaj B Agrawal 1,  Christopher R Pierson 2,  Mugdha Joshi 3,  Xiaoli Liu 4,  Gianina Ravenscroft 5,  Behzad Moghadaszadeh 3,  Tiffany Talabere 6,  Marissa Viola 7,  Lindsay C Swanson 3,  Göknur Haliloğlu 8,  Beril Talim 9,  Kyle S Yau 5,  Richard J N Allcock 10,  Nigel G Laing 5,  Mark A Perrella 11,  Alan H Beggs 12
Affiliations

Affiliations

  • 1 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 2 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus, OH 43205, USA.
  • 3 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston MA 02115, USA.
  • 5 Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
  • 6 Research Institute, Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus, OH 43205, USA.
  • 7 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 8 Neurology Unit, Department of Pediatrics, Hacettepe University Children's Hospital, Ankara 06100, Turkey.
  • 9 Pathology Unit, Department of Pediatrics, Hacettepe University Children's Hospital, Ankara 06100, Turkey.
  • 10 Lotterywest State Biomedical Facility Genomics and School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA 6009, Australia.
  • 11 Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston MA 02115, USA; Department of Newborn Medicine, Brigham and Women's Hospital, Boston MA 02115, USA.
  • 12 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 25087613 DOI: 10.1016/j.ajhg.2014.07.004
Abstract

Centronuclear myopathies (CNMs) are characterized by muscle weakness and increased numbers of central nuclei within myofibers. X-linked myotubular myopathy, the most common severe form of CNM, is caused by mutations in MTM1, encoding myotubularin (MTM1), a lipid Phosphatase. To increase our understanding of MTM1 function, we conducted a yeast two-hybrid screen to identify MTM1-interacting proteins. Striated muscle preferentially expressed protein kinase (SPEG), the product of SPEG complex locus (SPEG), was identified as an MTM1-interacting protein, confirmed by immunoprecipitation and immunofluorescence studies. SPEG knockout has been previously associated with severe dilated cardiomyopathy in a mouse model. Using whole-exome sequencing, we identified three unrelated CNM-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. SPEG was markedly reduced or absent in two individuals whose muscle was available for immunofluorescence and immunoblot studies. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. Our results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy.

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