PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue
Summary: PIEZO1 variants have been associated with generalized lymphatic dysplasia (GLD) through mechanisms involving reduced PIEZO1 expression. Here, we report variants where the mechanism involves reduced channel mechanical sensitivity. Two of the variants encode amino acid changes in the channel’...
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Elsevier
2025-08-01
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| author | Melanie J. Ludlow Oleksandr V. Povstyan Deborah M. Linley Silvia Martin-Almedina Charlotte Revill Kevin Cuthbertson Katie A. Smith Emily Fay Elisavet Fotiou Andrew Bush Claire Hogg Tobias Linden Natalie B. Tan Susan M. White Juan C. Del Rey Jimenez Ege Sackey Esther Dempsey Sahar Mansour Gregory Parsonage Antreas C. Kalli Richard Foster Pia Ostergaard David J. Beech |
| author_facet | Melanie J. Ludlow Oleksandr V. Povstyan Deborah M. Linley Silvia Martin-Almedina Charlotte Revill Kevin Cuthbertson Katie A. Smith Emily Fay Elisavet Fotiou Andrew Bush Claire Hogg Tobias Linden Natalie B. Tan Susan M. White Juan C. Del Rey Jimenez Ege Sackey Esther Dempsey Sahar Mansour Gregory Parsonage Antreas C. Kalli Richard Foster Pia Ostergaard David J. Beech |
| author_sort | Melanie J. Ludlow |
| collection | DOAJ |
| description | Summary: PIEZO1 variants have been associated with generalized lymphatic dysplasia (GLD) through mechanisms involving reduced PIEZO1 expression. Here, we report variants where the mechanism involves reduced channel mechanical sensitivity. Two of the variants encode amino acid changes in the channel’s cap structure (Ile2270Thr and Arg2335Gln), one in the ninth transmembrane helical unit (THU) below the cap (Gly1978Asp) and one in the fifth THU distant from the cap (Glu829Val). Patch-clamp studies of the cap and sub-cap variant channels revealed abolished or reduced channel mechanical sensitivity with the possibility to activate the channels and partly rescue mechanical sensitivity by the small molecule Yoda1. The potency of Yoda1 at the variant channels was less than at the wild-type channel, but chemical synthesis of Yoda1 analogs revealed a molecule with improved potency. The data suggest cases of GLD in which there is decreased channel mechanical sensitivity and the potential to reduce dysfunction pharmacologically. |
| format | Article |
| id | doaj-art-95ee7927cd034e8f9d2b267877a1c601 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-95ee7927cd034e8f9d2b267877a1c6012025-08-20T02:52:42ZengElsevieriScience2589-00422025-08-0128811311010.1016/j.isci.2025.113110PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescueMelanie J. Ludlow0Oleksandr V. Povstyan1Deborah M. Linley2Silvia Martin-Almedina3Charlotte Revill4Kevin Cuthbertson5Katie A. Smith6Emily Fay7Elisavet Fotiou8Andrew Bush9Claire Hogg10Tobias Linden11Natalie B. Tan12Susan M. White13Juan C. Del Rey Jimenez14Ege Sackey15Esther Dempsey16Sahar Mansour17Gregory Parsonage18Antreas C. Kalli19Richard Foster20Pia Ostergaard21David J. Beech22Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UKSchool of Health & Medical Sciences, City St George’s, University of London, London SW17 0RE, UKSchool of Chemistry, University of Leeds, Leeds LS2 9JT, UKSchool of Chemistry, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UKSchool of Health & Medical Sciences, City St George’s, University of London, London SW17 0RE, UKSchool of Health & Medical Sciences, City St George’s, University of London, London SW17 0RE, UKPaediatric Respiratory Medicine, NHLI, Imperial College London, London, UK; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UKPaediatric Respiratory Medicine, NHLI, Imperial College London, London, UK; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UKDepartment of Neuropediatrics, University Children’s Hospital, Klinikum Oldenburg, Oldenburg, GermanyVictorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, AustraliaVictorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, AustraliaSouth West Thames Regional Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UKSouth West Thames Regional Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UKSchool of Health & Medical Sciences, City St George’s, University of London, London SW17 0RE, UK; South West Thames Regional Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UKSchool of Health & Medical Sciences, City St George’s, University of London, London SW17 0RE, UK; South West Thames Regional Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UKSchool of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Corresponding authorSchool of Health & Medical Sciences, City St George’s, University of London, London SW17 0RE, UK; Corresponding authorLeeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK; Corresponding authorSummary: PIEZO1 variants have been associated with generalized lymphatic dysplasia (GLD) through mechanisms involving reduced PIEZO1 expression. Here, we report variants where the mechanism involves reduced channel mechanical sensitivity. Two of the variants encode amino acid changes in the channel’s cap structure (Ile2270Thr and Arg2335Gln), one in the ninth transmembrane helical unit (THU) below the cap (Gly1978Asp) and one in the fifth THU distant from the cap (Glu829Val). Patch-clamp studies of the cap and sub-cap variant channels revealed abolished or reduced channel mechanical sensitivity with the possibility to activate the channels and partly rescue mechanical sensitivity by the small molecule Yoda1. The potency of Yoda1 at the variant channels was less than at the wild-type channel, but chemical synthesis of Yoda1 analogs revealed a molecule with improved potency. The data suggest cases of GLD in which there is decreased channel mechanical sensitivity and the potential to reduce dysfunction pharmacologically.http://www.sciencedirect.com/science/article/pii/S2589004225013719PharmacologyCell biology |
| spellingShingle | Melanie J. Ludlow Oleksandr V. Povstyan Deborah M. Linley Silvia Martin-Almedina Charlotte Revill Kevin Cuthbertson Katie A. Smith Emily Fay Elisavet Fotiou Andrew Bush Claire Hogg Tobias Linden Natalie B. Tan Susan M. White Juan C. Del Rey Jimenez Ege Sackey Esther Dempsey Sahar Mansour Gregory Parsonage Antreas C. Kalli Richard Foster Pia Ostergaard David J. Beech PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue iScience Pharmacology Cell biology |
| title | PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue |
| title_full | PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue |
| title_fullStr | PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue |
| title_full_unstemmed | PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue |
| title_short | PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue |
| title_sort | piezo1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue |
| topic | Pharmacology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225013719 |
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