MFN2 – Multiple Symmetric Lipomatosis

Multiple symmetric lipomatosis (MSL) is a rare mitochondrial lipodystrophic syndrome characterized by symmetric upper‐body lipomatous masses frequently accompanied by peripheral neuropathy. Recent studies implicate homozygous MFN2 variants as a novel cause of MSL in patients lacking the classical MERRF mutations. This summary evaluates evidence linking MFN2 (HGNC:16877) to MSL (MONDO_0007908) for clinical and research applications.

Genetic data support an autosomal recessive inheritance with segregation in affected families. Whole‐exome sequencing in a sibling pair and an unrelated individual identified the same homozygous c.2119C>T (p.Arg707Trp) variant in three probands from two independent pedigrees; this variant was absent in healthy siblings ([PMID:26085578]). A targeted screen of 66 patients with altered fat distribution uncovered six additional individuals from five families harboring homozygous p.Arg707Trp, confirming a recurrent allele in MSL cohorts ([PMID:30158064]).

Functional assays demonstrate that p.Arg707Trp impairs MFN2 homotypic interactions essential for mitochondrial fusion, resulting in perinuclear mitochondrial aggregation in patient fibroblasts ([PMID:26085578]). Histological and molecular analysis of lipomatous tissue reveals adipocyte hyperplasia with mitochondrial proliferation and structural defects, marked decreases in leptin and adiponectin expression, elevated FGF21 levels, and increased 18F‐FDG uptake, underscoring mitochondrial dysfunction in vivo ([PMID:30158064]). An induced pluripotent stem cell line carrying homozygous c.2119C>T recapitulates these defects and provides a model for mechanistic studies ([PMID:32916636]).

No conflicting reports have been described. The aggregate genetic and experimental evidence support a Moderate level of clinical validity for MFN2 in MSL.

Key Take-home: Homozygous MFN2 p.Arg707Trp causes an autosomal recessive mitochondrial lipodystrophic syndrome, informing diagnosis, genetic counseling, and future therapeutic research.

References

• Human Molecular Genetics • 2015 • Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy. PMID:26085578
• Journal of Clinical Lipidology • 2018 • MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue. PMID:30158064
• Stem Cell Research • 2020 • Establishment of a human induced pluripotent stem cell line, JUCTCi012-A, from multiple symmetric lipomatosis (MSL) patient carrying a homozygous Arg707Trp (c.2119C>T) mutation in the MFN2 gene. PMID:32916636

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