PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue

Year: 2025

Type: article

Abstract: 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.

Source: iScience

DOI: 10.1016/j.isci.2025.113110

Institutions: University of Leeds, City St George's, University of London, Royal Brompton Hospital, Imperial College London, Klinikum Oldenburg, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, St George’s University Hospitals NHS Foundation Trust

Language: English

Topic: Erythrocyte Function and Pathophysiology

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,240

Funders: Wellcome Trust, Newlife the Charity for Disabled Children, National Institute for Health and Care Research, British Heart Foundation, University of Leeds, Medical Research Council, NIHR Imperial Biomedical Research Centre, Leeds Biomedical Research Centre

Awards: G1114017013, Understanding vascular mechanical sensitivity., Deep phenotyping to improve understanding of causal mechanisms and underlying gene mutations in primary lymphoedema and lymphatic malformations, Endothelial Piezo1 channel in whole body physical activity and cardio-metabolic protection, Joint funding with MRC: Deep phenotyping to improve understanding of causal mechanisms and underlying gene mutations in primary lymphoedema and lymphatic malformations, G4369440824, G4566385481, Understanding vascular mechanical sensitivity., G6697820746, Leeds 4th intake 2020 – 4-year PhD Studentship (4th) Scheme: Ms Eva Clavane; Ms Manon Owen; Ms Katie Smith; Ms Hannah Taylor, Functional analysis of GATA2 and KIF11: newly identified genes for primary lymphoedema

OpenAlex ID: W4412458846