An Isogenic iPSC Model of LMNA p.R482W Recapitulates Adipocyte Dysfunction in Familial Partial Lipodystrophy Type 2

CRISPR/Cas9-edited isogenic iPSC-derived adipocytes carrying LMNA c.1444C>T (p.R482W) show severe insulin resistance and reduced metabolism, with oxygen consumption dropping to 126.5 vs 261.5 pmol/min.

• Why it matters: FPLD2 adipocyte dysfunction mechanisms are unclear because prior in vitro models use non-isogenic lines or require non-physiologic transgene overexpression, limiting mechanistic interpretation.
• What they did: A transgene-free mesenchymal progenitor differentiation protocol generated LMNAp.R482W and isogenic control adipocytes, followed by bulk RNA-seq, glucose uptake assays, and Seahorse extracellular flux analysis.
• The result: Despite strong adipogenesis gene concordance during differentiation (Pearson rho = 0.968), LMNAp.R482W adipocytes downregulate adipogenic, lipid-handling, and extracellular matrix genes and match human subcutaneous white adipose tissue across 37 pathways with 59.5% concordance.

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