Format

Send to

Choose Destination
Am J Hum Genet. 2014 Aug 7;95(2):218-26. doi: 10.1016/j.ajhg.2014.07.004. Epub 2014 Jul 31.

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

Author information

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: pagrawal@enders.tch.harvard.edu.
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: beggs@enders.tch.harvard.edu.

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.

PMID:
25087613
PMCID:
PMC4129406
DOI:
10.1016/j.ajhg.2014.07.004
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center