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Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPAR? deficiency.


ABSTRACT: Familial partial lipodystrophy (FPLD) is characterized by abnormal fat distribution and a metabolic syndrome with hypertriglyceridemia. We identified a family with a severe form of FPLD3 with never-reported clinical features and a novel mutation affecting the DNA binding domain of PPAR? (E157D). Apart from the lipodystrophy and severe metabolic syndrome, individuals presented musculoskeletal and hematological issues. E157D heterozygotes had a muscular habitus yet displayed muscle weakness and myopathy. Also, E157D heterozygotes presented multiple cytopenias and a susceptibility to autoimmune disease. In vitro studies showed that the E157D mutation does not decrease the receptor's affinity to classical PPAR response elements or its responsiveness to a PPAR? agonist, yet it severely reduces its target gene transcription. Microarray experiments demonstrated a decreased activation of a wide array of genes, including genes involved in the PPAR response, the immune response, hematopoiesis, and metabolism in muscle. In addition, a subset of genes with cryptic PPAR response elements was activated. In summary, we describe a large family with a novel PPAR? mutation, which extends the clinical phenotype of FPLD3 to include muscular, immune, and hematological features. Together, our results support the role of PPAR? in controlling homeostasis of multiple systems beyond lipid metabolism.

SUBMITTER: Campeau PM 

PROVIDER: S-EPMC3413236 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency.

Campeau Philippe M PM   Astapova Olga O   Martins Rebecca R   Bergeron Jean J   Couture Patrick P   Hegele Robert A RA   Leff Todd T   Gagné Claude C  

Journal of lipid research 20120702 9


Familial partial lipodystrophy (FPLD) is characterized by abnormal fat distribution and a metabolic syndrome with hypertriglyceridemia. We identified a family with a severe form of FPLD3 with never-reported clinical features and a novel mutation affecting the DNA binding domain of PPARγ (E157D). Apart from the lipodystrophy and severe metabolic syndrome, individuals presented musculoskeletal and hematological issues. E157D heterozygotes had a muscular habitus yet displayed muscle weakness and my  ...[more]

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