Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling PMID: 37919452

ADC Targets in Oncology

2026-04-10

Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling

Nat Genet. 2023 Nov;55(11):1929-1940. doi: 10.1038/s41588-023-01535-3.

Nika Schuermans ^# ¹ ² , Salima El Chehadeh ^# ³ ⁴ ⁵ , Dimitri Hemelsoet ^# ⁶ , Jérémie Gautheron ^# ⁷ , Marie-Christine Vantyghem ⁸ ⁹ , Sonia Nouioua ¹⁰ ¹¹ , Meriem Tazir ¹¹ ¹² , Corinne Vigouroux ⁷ ¹³ , Martine Auclair ⁷ ¹³ , Elke Bogaert ¹ ² , Sara Dufour ² ¹⁴ ¹⁵ , Fumiya Okawa ¹⁶ , Pascale Hilbert ¹⁷ , Nike Van Doninck ¹⁸ , Marie-Caroline Taquet ¹⁹ , Toon Rosseel ¹ , Griet De Clercq ¹ ² , Elke Debackere ¹ ² , Carole Van Haverbeke ²⁰ , Ferroudja Ramdane Cherif ¹⁰ ¹¹ , Jon Andoni Urtizberea ²¹ , Jean-Baptiste Chanson ²² , Benoit Funalot ²³ ²⁴ , François-Jérôme Authier ²⁴ ²⁵ , Sabine Kaya ²⁶ , Wim Terryn ²⁷ , Steven Callens ²⁸ , Bernard Depypere ²⁹ , Jo Van Dorpe ²⁰ , Program for Undiagnosed Diseases (UD-PrOZA) , Bruce Poppe ¹ ² , Francis Impens ² ¹⁴ ¹⁵ , Noboru Mizushima ¹⁶ , Christel Depienne ⁴ ²⁶ , Isabelle Jéru ⁷ ³⁰ , Bart Dermaut ³¹ ³²

Affiliations

1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
2. Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
3. Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
4. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS-UMR7104, Université de Strasbourg, Strasbourg, France.
5. Laboratoire de Génétique Médicale, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg et INSERM, Strasbourg, France.
6. Department of Neurology, Ghent University Hospital, Ghent, Belgium.
7. Sorbonne Université, INSERM UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
8. Endocrinology, Diabetology, Metabolism Department, National Competence Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Lille University Hospital, Lille, France.
9. University of Lille, INSERM U1190, European Genomic Institute for Diabetes, Lille, France.
10. Department of Neurology of the EHS of Cherchell, University Centre of Blida, Tipaza, Algeria.
11. NeuroSciences Research Laboratory, University of Algiers Benyoucef Benkhedda, Algiers, Algeria.
12. Department of Neurology, CHU Algiers (Mustapha Pacha Hospital), Algiers, Algeria.
13. Assistance Publique-Hôpitaux de Paris, Saint-Antoine University Hospital, National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Department of Endocrinology, Diabetology and Reproductive Endocrinology, and Department of Molecular Biology and Genetics, Paris, France.
14. VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
15. VIB Proteomics Core, VIB, Ghent, Belgium.
16. Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Bunkyo, Japan.
17. Department of Molecular and Cellular Biology, Institute of Pathology and Genetics, Charleroi, Belgium.
18. Department of Endocrinology and Diabetology, General Hospital VITAZ, Sint-Niklaas, Belgium.
19. Department of Internal Medicine and Nutrition, Hopitaux Universitaires Strasbourg, Strasbourg, France.
20. Department of Pathology, Ghent University Hospital, Ghent, Belgium.
21. Institut de Myologie, Paris, France.
22. Service de Neurologie et Centre de Référence Neuromusculaire Nord/Est/Ile de France, Hôpital de Hautepierre, Strasbourg, France.
23. Department of Medical Genetics, Hôpital Henri Mondor, Université Paris-Est-Créteil, Créteil, France.
24. INSERM UMR955, Team Relaix, Faculty of Medicine, Créteil, France.
25. Centre Expert de Pathologie Neuromusculaire/Histologie, Département de Pathologie, Hôpital Henri Mondor, Université Paris-Est-Créteil, Créteil, France.
26. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
27. Department of Nephrology, Jan Yperman Hospital, Ieper, Belgium.
28. Department of General Internal Medicine, Ghent University Hospital, Ghent, Belgium.
29. Department of Plastic and Reconstructive Surgery, Ghent University Hospital, Ghent, Belgium.
30. Department of Medical Genetics, DMU BioGeM, Sorbonne Université, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
31. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. [email protected].
32. Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. [email protected].
# Contributed equally.

Abstract

Phospholipase A/Acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3^-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane Phospholipids and a strong decrease in the signaling of Peroxisome Proliferator-activated Receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced Insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.