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Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia

Author

Listed:
  • Viktor Lukacs

    (Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute)

  • Jayanti Mathur

    (Genomics Institute of the Novartis Research Foundation)

  • Rong Mao

    (ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories
    University of Utah)

  • Pinar Bayrak-Toydemir

    (ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories
    University of Utah)

  • Melinda Procter

    (ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories)

  • Stuart M. Cahalan

    (Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute)

  • Helen J. Kim

    (Integrative Structural and Computational Biology, The Scripps Research Institute)

  • Michael Bandell

    (Genomics Institute of the Novartis Research Foundation)

  • Nicola Longo

    (University of Utah)

  • Ronald W. Day

    (University of Utah)

  • David A. Stevenson

    (University of Utah
    Stanford University)

  • Ardem Patapoutian

    (Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute)

  • Bryan L. Krock

    (ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories
    University of Utah
    The Children’s Hospital of Philadelphia
    Perelman School of Medicine, University of Pennsylvania)

Abstract

Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients’ erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.

Suggested Citation

  • Viktor Lukacs & Jayanti Mathur & Rong Mao & Pinar Bayrak-Toydemir & Melinda Procter & Stuart M. Cahalan & Helen J. Kim & Michael Bandell & Nicola Longo & Ronald W. Day & David A. Stevenson & Ardem Pat, 2015. "Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia," Nature Communications, Nature, vol. 6(1), pages 1-7, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9329
    DOI: 10.1038/ncomms9329
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    Cited by:

    1. Waheed-Ul-Rahman Ahmed & Sam Kleeman & Michael Ng & Wei Wang & Adam Auton & Regent Lee & Ashok Handa & Krina T. Zondervan & Akira Wiberg & Dominic Furniss, 2022. "Genome-wide association analysis and replication in 810,625 individuals with varicose veins," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Francisco Andrés Peralta & Mélaine Balcon & Adeline Martz & Deniza Biljali & Federico Cevoli & Benoit Arnould & Antoine Taly & Thierry Chataigneau & Thomas Grutter, 2023. "Optical control of PIEZO1 channels," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Sebastian Jojoa-Cruz & Kei Saotome & Che Chun Alex Tsui & Wen-Hsin Lee & Mark S. P. Sansom & Swetha E. Murthy & Ardem Patapoutian & Andrew B. Ward, 2022. "Structural insights into the Venus flytrap mechanosensitive ion channel Flycatcher1," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Sine Yaganoglu & Konstantinos Kalyviotis & Christina Vagena-Pantoula & Dörthe Jülich & Benjamin M. Gaub & Maaike Welling & Tatiana Lopes & Dariusz Lachowski & See Swee Tang & Armando Del Rio Hernandez, 2023. "Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Nathalia G. Amado & Elena D. Nosyreva & David Thompson & Thomas J. Egeland & Osita W. Ogujiofor & Michelle Yang & Alexandria N. Fusco & Niccolo Passoni & Jeremy Mathews & Brandi Cantarel & Linda A. Ba, 2024. "PIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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