eLife (Apr 2017)
Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression
- Nuno Rocha,
- David A Bulger,
- Andrea Frontini,
- Hannah Titheradge,
- Sigrid Bjerge Gribsholt,
- Rachel Knox,
- Matthew Page,
- Julie Harris,
- Felicity Payne,
- Claire Adams,
- Alison Sleigh,
- John Crawford,
- Anette Prior Gjesing,
- Jette Bork-Jensen,
- Oluf Pedersen,
- Inês Barroso,
- Torben Hansen,
- Helen Cox,
- Mary Reilly,
- Alex Rossor,
- Rebecca J Brown,
- Simeon I Taylor,
- Duncan McHale,
- Martin Armstrong,
- Elif A Oral,
- Vladimir Saudek,
- Stephen O’Rahilly,
- Eamonn R Maher,
- Bjørn Richelsen,
- David B Savage,
- Robert K Semple
Affiliations
- Nuno Rocha
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- David A Bulger
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
- Andrea Frontini
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
- Hannah Titheradge
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom; West Midlands Medical Genetics Department, Birmingham Women’s Hospital, Edgbaston, Birmingham, United Kingdom
- Sigrid Bjerge Gribsholt
- Department of Endocrinology and Internal Medicine and Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
- Rachel Knox
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Matthew Page
- New Medicines, UCB Pharma, Slough, United Kingdom
- Julie Harris
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Felicity Payne
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Claire Adams
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Alison Sleigh
- Wolfson Brain Imaging Centre, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom
- John Crawford
- Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Anette Prior Gjesing
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Jette Bork-Jensen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Inês Barroso
- ORCiD
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Helen Cox
- West Midlands Medical Genetics Department, Birmingham Women’s Hospital, Edgbaston, Birmingham, United Kingdom
- Mary Reilly
- MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom
- Alex Rossor
- MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom
- Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
- Simeon I Taylor
- University of Maryland School of Medicine, Baltimore, United States
- Duncan McHale
- New Medicines, UCB Pharma, Slough, United Kingdom
- Martin Armstrong
- New Medicines, UCB Pharma, Slough, United Kingdom
- Elif A Oral
- Metabolism, Endocrinology and Diabetes (MEND) Division, Department of Internal of Medicine, Brehm Center for Diabetes, Ann Arbor, United States
- Vladimir Saudek
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Stephen O’Rahilly
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Eamonn R Maher
- The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom; Department of Medical Genetics, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
- Bjørn Richelsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Clinical Medicine, Aarhus University, Aarhus, Denmark
- David B Savage
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Robert K Semple
- ORCiD
- The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- DOI
- https://doi.org/10.7554/eLife.23813
- Journal volume & issue
-
Vol. 6
Abstract
MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.
Keywords