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The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy

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Abstract

Aims

Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations.

Methods

Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation.

Results

We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30–35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor.

Conclusions

Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.

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Funding

This work was partly supported by the Italian Ministry of Health (Ricerca Corrente 2018-2020 to SP and VT).

Author information

Author notes

  1. Emanuele Bellacchio

    Present address: Research Laboratories, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

  2. Giuseppa Padova and Sabrina Prudente have contributed equally to this work.

Authors and Affiliations

  1. Endocrinology Unit, Garibaldi Hospital, Catania, Italy

    Giuseppa Padova, Roberto Baratta, Laura Sciacca & Lucia Frittitta

  2. Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

    Sabrina Prudente & Vincenzo Trischitta

  3. Endocrine Section, Department of Clinical and Experimental Medicine, University of Catania, Via Palermo 636, 95122, Catania, Italy

    Federica Vinciguerra, Dora Sudano, Laura Sciacca & Lucia Frittitta

  4. Bioinformatics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

    Emanuele Bellacchio

  5. Department of Experimental Medicine, “Sapienza” University, Rome, Italy

    Vincenzo Trischitta

  6. Radiology Unit, Garibaldi Hospital, Catania, Italy

    Antonino Vallone

Authors
  1. Giuseppa Padova
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  2. Sabrina Prudente
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  3. Federica Vinciguerra
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  4. Dora Sudano
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  5. Roberto Baratta
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  6. Emanuele Bellacchio
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  7. Vincenzo Trischitta
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  8. Antonino Vallone
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  9. Laura Sciacca
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  10. Lucia Frittitta
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Contributions

GP, SP and LF designed the study, analyzed data and wrote the manuscript. FV, DS, RB, EB, AV and LS generated and analyzed data. VT analyzed data and helped writing the manuscript. All authors read and commented on the manuscript. LF is the guarantor of this work and had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis.

Corresponding author

Correspondence to Lucia Frittitta.

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Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (University of Catania and IRCCS Casa Sollievo della Sofferenza, Italy) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent

Informed consent was obtained from all patients or their relatives for being included in the study.

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Padova, G., Prudente, S., Vinciguerra, F. et al. The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy. Acta Diabetol 57, 589–596 (2020). https://doi.org/10.1007/s00592-019-01462-y

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  • DOI: https://doi.org/10.1007/s00592-019-01462-y

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