Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression
- The University of Cambridge Metabolic Research Laboratories, United Kingdom
- University of Pavia, Italy
- University of Birmingham, United Kingdom
- Aarhus University Hospital, Denmark
- UCB Pharma, United Kingdom
- Wellcome Trust Sanger Institute, United Kingdom
- University of Cambridge School of Clinical Medicine, United Kingdom
- Cambridge University Hospitals NHS Foundation Trust, United Kingdom
- University of Copenhagen, Denmark
- Birmingham Women's Hospital, United Kingdom
- UCL Institute of Neurology, United Kingdom
- National Institutes of Health, United States
- University of Maryland School of Medicine, United States
- Brehm Center for Diabetes, United States
- The National Institute for Health Research Cambridge Biomedical Research Centre, United Kingdom
- Aarhus University, Denmark
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.
Data availability
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RNA-seq of overgrown interscapular adipose tissue with biallelic MFN2 mutationsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE97156).
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ClinVar: public archive of interpretations of clinically relevant variantsPublicly available at the NCBI ClinVar (accession no: RCV000002369).
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Exome Aggregation Consortium (ExAC)Publicly available at Broad Institute (accession no: ENSG00000116688).
Article and author information
Author details
Funding
Medical Research Council (MRC_MC_UU_12012/5)
- Nuno M Rocha
Wellcome (Wellcome Trust Postdoctoral Fellowship for Clinicians (10043/Z/15/Z))
- Alex Rossor
National Institute for Health Research (NIHR Clinical Research Facilities for Experimental Medicine Award to Cambridge NIHR/Wellcome Trust)
- Alison Sleigh
National Institute for Health Research (Cambridge BRC and Clinical Research Facility; Rare Disease Translational Research Collaboration)
- Stephen I O'Rahilly
- Eamonn R Maher
- David B Savage
- Robert K Semple
National Institutes of Health (Oxford-Cambridge Scholars Programme)
- David A Bulger
Wellcome (WT098051)
- Felicity Payne
- Inês Barroso
National Institute of Diabetes and Digestive and Kidney Diseases (Intramural research program)
- Elif A Oral
National Institute of Diabetes and Digestive and Kidney Diseases (RO1-DK 08811)
- Elif A Oral
UCB Pharma (Gen 001)
- Hannah Titheradge
- Duncan McHale
- Eamonn R Maher
Medical Research Council (MRC Centre grant (G0601943))
- Mary Reilly
National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712)
- Mary Reilly
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Written informed consent was obtained from all participants or their parents if under 18 years old for the research described and for publication of results. The research was approved by the Cambridgeshire South Research Ethics Committee, Reference no. 12/EE/0405
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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