PPARG – PPARG-related Familial Partial Lipodystrophy Type 3

Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder characterized by loss of subcutaneous adipose tissue in the limbs with central fat accumulation, severe insulin resistance, hypertriglyceridemia and hypertension. Patients often develop diabetes mellitus, fatty liver and albuminuria in adolescence or early adulthood. Clinical diagnosis should prompt molecular testing of PPARG in the absence of LMNA mutations to guide management and therapeutic decisions.

Genetic evidence for PPARG in FPLD3 includes a pedigree of five affected individuals segregating a novel heterozygous PPARG c.1040A>C (p.Lys347Thr) variant (PMID:26119484) and a Canadian kindred with Y355X nonsense mutations in two generations (PMID:16412238), totaling seven segregations. A cohort of 58 unrelated FPLD3 patients further defined the phenotypic spectrum (PMID:35422762), and cross-sectional comparison with 196 FPLD2 subjects confirmed distinct metabolic profiles in 32 FPLD3 individuals (PMID:36397776). Additionally, 6/182 patients with severe hypertriglyceridemia were reclassified as FPLD3 based on PPARG pathogenic variants (PMID:40615268).

The variant spectrum includes missense changes clustering in the DNA-binding and ligand-binding domains, nonsense and splice-site mutations, and frameshifts, with both haploinsufficiency and dominant-negative mechanisms described. A representative pathogenic allele is c.1040A>C (p.Lys347Thr). No recurrent founder variants have been reported, and prevalence estimates suggest PPARG mutations occur in ~1 in 500 individuals, although FPLD3 remains underdiagnosed.

Functional assays across multiple studies demonstrate that PPARG mutants exhibit reduced transcriptional activity, impaired DNA binding, altered co-factor recruitment, and dominant-negative interference with the wild-type receptor. Rescue experiments with thiazolidinedione agonists such as rosiglitazone and pioglitazone partially restore function in selected mutants, corroborating a mechanism of haploinsufficiency and providing a rationale for tailored therapies (PMID:29622583).

No conflicting evidence refutes PPARG as the causative gene for FPLD3. The concordance of genetic segregation, multiple unrelated case series, and consistent functional disruptions over nearly two decades support a definitive gene–disease relationship.

Key Take-home: PPARG mutations cause FPLD3 via loss-of-function and dominant-negative effects, warranting genetic testing in patients with partial lipodystrophy and enabling precision use of PPARγ agonists.

References

• Clinical Endocrinology • 2016 • Novel peroxisome proliferator-activated receptor gamma mutation in a family with familial partial lipodystrophy type 3. PMID:26119484
• BMC Medical Genetics • 2006 • Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3). PMID:16412238
• Frontiers in Endocrinology • 2022 • Case Report: A New Peroxisome Proliferator-Activated Receptor Gamma Mutation Causes Familial Partial Lipodystrophy Type 3 in a Chinese Patient. PMID:35422762
• Journal of the Endocrine Society • 2022 • Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants. PMID:36397776
• Journal of Clinical Lipidology • 2025 • Heterozygous pathogenic PPARG variants in patients with severe hypertriglyceridemia. PMID:40615268
• Diabetes • 2018 • A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations. PMID:29622583

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