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

Nika Schuermans (UGent) , Salima El Chehadeh, Dimitri Hemelsoet (UGent) , Jérémie Gautheron, Marie-Christine Vantyghem, Sonia Nouioua, Meriem Tazir, Corinne Vigouroux, Martine Auclair, Elke Bogaert (UGent) , et al.
(2023) NATURE GENETICS. 55(11). p.1929-1940
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Abstract
hospholipase 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 (PPAR gamma), 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 PPAR gamma. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPAR gamma-dependent defect in WAT differentiation and function. Homozygous loss-of-function variants in phospholipase A/acyltransferase 3 (PLAAT3) underlie a new lipodystrophy syndrome. Functional studies link PLAAT3 loss with peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated defects in white adipose tissue differentiation and function.
Keywords
SEVERE INSULIN-RESISTANCE, DROSOPHILA-MELANOGASTER, TARGET GENE, IDENTIFICATION, MUTATIONS, DISCOVERY, DIAGNOSIS, ALIGNMENT, VARIANTS, PROGRAM

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Citation

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MLA
Schuermans, Nika, et al. “Loss of Phospholipase PLAAT3 Causes a Mixed Lipodystrophic and Neurological Syndrome Due to Impaired PPARγ Signaling.” NATURE GENETICS, vol. 55, no. 11, 2023, pp. 1929–40, doi:10.1038/s41588-023-01535-3.
APA
Schuermans, N., El Chehadeh, S., Hemelsoet, D., Gautheron, J., Vantyghem, M.-C., Nouioua, S., … Dermaut, B. (2023). Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling. NATURE GENETICS, 55(11), 1929–1940. https://doi.org/10.1038/s41588-023-01535-3
Chicago author-date
Schuermans, Nika, Salima El Chehadeh, Dimitri Hemelsoet, Jérémie Gautheron, Marie-Christine Vantyghem, Sonia Nouioua, Meriem Tazir, et al. 2023. “Loss of Phospholipase PLAAT3 Causes a Mixed Lipodystrophic and Neurological Syndrome Due to Impaired PPARγ Signaling.” NATURE GENETICS 55 (11): 1929–40. https://doi.org/10.1038/s41588-023-01535-3.
Chicago author-date (all authors)
Schuermans, Nika, Salima El Chehadeh, Dimitri Hemelsoet, Jérémie Gautheron, Marie-Christine Vantyghem, Sonia Nouioua, Meriem Tazir, Corinne Vigouroux, Martine Auclair, Elke Bogaert, Sara Dufour, Fumiya Okawa, Pascale Hilbert, Nike Van Doninck, Marie-Caroline Taquet, Toon Rosseel, Griet De Clercq, Elke Debackere, Carole Van Haverbeke, Ferroudja Ramdane Cherif, Jon Andoni Urtizberea, Jean-Baptiste Chanson, Benoit Funalot, François-Jérôme Authier, Sabine Kaya, Wim Terryn, Steven Callens, Bernard Depypere, Jo Van Dorpe, Arnaud Vanlander, PATRICK VERLOO, Paul Coucke, Program Undiagnosed Dis UD PrOZA, Bruce Poppe, Francis Impens, Noboru Mizushima, Christel Depienne, Isabelle Jéru, and Bart Dermaut. 2023. “Loss of Phospholipase PLAAT3 Causes a Mixed Lipodystrophic and Neurological Syndrome Due to Impaired PPARγ Signaling.” NATURE GENETICS 55 (11): 1929–1940. doi:10.1038/s41588-023-01535-3.
Vancouver
1.
Schuermans N, El Chehadeh S, Hemelsoet D, Gautheron J, Vantyghem M-C, Nouioua S, et al. Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling. NATURE GENETICS. 2023;55(11):1929–40.
IEEE
[1]
N. Schuermans et al., “Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling,” NATURE GENETICS, vol. 55, no. 11, pp. 1929–1940, 2023.
@article{01HFBMQ61SGP3NC5AVXFJDXFGF,
  abstract     = {{hospholipase 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 (PPAR gamma), 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 PPAR gamma. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPAR gamma-dependent defect in WAT differentiation and function.

Homozygous loss-of-function variants in phospholipase A/acyltransferase 3 (PLAAT3) underlie a new lipodystrophy syndrome. Functional studies link PLAAT3 loss with peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated defects in white adipose tissue differentiation and function.}},
  author       = {{Schuermans, Nika and El Chehadeh, Salima and Hemelsoet, Dimitri and Gautheron, Jérémie and Vantyghem, Marie-Christine and Nouioua, Sonia and Tazir, Meriem and Vigouroux, Corinne and Auclair, Martine and Bogaert, Elke and Dufour, Sara and Okawa, Fumiya and Hilbert, Pascale and Van Doninck, Nike and Taquet, Marie-Caroline and Rosseel, Toon and De Clercq, Griet and Debackere, Elke and Van Haverbeke, Carole and Cherif, Ferroudja Ramdane and Urtizberea, Jon Andoni and Chanson, Jean-Baptiste and Funalot, Benoit and Authier, François-Jérôme and Kaya, Sabine and Terryn, Wim and Callens, Steven and Depypere, Bernard and Van Dorpe, Jo and Vanlander, Arnaud and VERLOO, PATRICK and Coucke, Paul and Undiagnosed Dis UD PrOZA, Program and Poppe, Bruce and Impens, Francis and Mizushima, Noboru and Depienne, Christel and Jéru, Isabelle and Dermaut, Bart}},
  issn         = {{1061-4036}},
  journal      = {{NATURE GENETICS}},
  keywords     = {{SEVERE INSULIN-RESISTANCE,DROSOPHILA-MELANOGASTER,TARGET GENE,IDENTIFICATION,MUTATIONS,DISCOVERY,DIAGNOSIS,ALIGNMENT,VARIANTS,PROGRAM}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{1929--1940}},
  title        = {{Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling}},
  url          = {{http://doi.org/10.1038/s41588-023-01535-3}},
  volume       = {{55}},
  year         = {{2023}},
}
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