Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy

Sarah L. Sawyer, Andy Cheuk-Him Ng, A. Micheil Innes, Justin D. Wagner, David A. Dyment, Martine Tetreault, Jacek Majewski, Kym M. Boycott, Robert A. Screaton, Garth Nicholson

Multiple symmetric lipomatosis (MSL) is a mitochondrial disorder with impaired brown fat metabolism that has been associated with MERFF mutations in some, but not all patients. We studied a sibling pair and an unrelated individual who presented with multiple symmetric lipomatosis (MSL) and neuropathy to determine the genetic etiology of this disorder in patients who did not carry the MSL-associated MERFF mutation. Whole exome sequencing was performed on the siblings and a rare, shared homozygous mutation in MFN2 (c.2119C>T: p.R707W) was identified. The mutation was not present in their healthy siblings. In silico programs predict it to be pathogenic and heterozygous carriers of the MFN2 p.R707W substitution are known to have Charcot-Marie-Tooth disease (CMT). A third, unrelated, patient with multiple symmetrical lipomatosis and neuropathy also harbored the same homozygous mutation and had been previously diagnosed with CMT. Functional studies in patient fibroblasts demonstrate that the p.R707W substitution impairs homotypic (MFN2-MFN2) protein interactions required for normal activity, and renders mitochondria prone to perinuclear aggregation. These findings show that homozygous mutations at p.R707W in MFN2 are a novel cause of multiple symmetrical lipomatosis.