{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:07:00Z","timestamp":1787663220752,"version":"build-2736575974"},"posted":{"date-parts":[[2023,7,24]]},"group-title":"Genetics","reference-count":61,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR\/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant\n                  <jats:italic>pezo-1[R2405P]<\/jats:italic>\n                  that in human\n                  <jats:italic>PIEZO2<\/jats:italic>\n                  causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that\n                  <jats:italic>pezo-1(R2405P)<\/jats:italic>\n                  is a gain-of-function allele. Using genomic mapping and whole genome sequencing approaches, we identified a candidate suppressor allele in the\n                  <jats:italic>C. elegans<\/jats:italic>\n                  gene\n                  <jats:italic>gex-3.<\/jats:italic>\n                  This gene is an ortholog of human\n                  <jats:italic>NCKAP1<\/jats:italic>\n                  (NCK-associated protein 1), a subunit of the Wiskott-Aldrich syndrome protein (WASP)-verprolin homologous protein (WAVE\/SCAR) complex, which regulates F-actin polymerization. Depletion of\n                  <jats:italic>gex-3<\/jats:italic>\n                  by RNAi, or with the suppressor allele\n                  <jats:italic>gex-3(av259[L353F])<\/jats:italic>\n                  , significantly restored the small brood size and low ovulation rate, as well as alleviated the crushed oocyte phenotype of the\n                  <jats:italic>pezo-1(R2405P)<\/jats:italic>\n                  mutant. Auxin-inducible degradation of GEX-3 revealed that only somatic-specific degradation of GEX-3 restored the reduced brood size in the\n                  <jats:italic>pezo-1(R2405P)<\/jats:italic>\n                  mutants. Additionally, actin organization and orientation were disrupted and distorted in the\n                  <jats:italic>pezo-1<\/jats:italic>\n                  mutants. Mutation of\n                  <jats:italic>gex-3(L353F)<\/jats:italic>\n                  partially alleviated these defects. The identification of\n                  <jats:italic>gex-3<\/jats:italic>\n                  as a suppressor of the pathogenic variant\n                  <jats:italic>pezo-1(R2405P)<\/jats:italic>\n                  suggests that the cytoskeleton plays an important role in regulating PIEZO channel activity and provides insight into the molecular mechanisms of DA5 and other PIEZO-associated diseases.\n                <\/jats:p>","DOI":"10.1101\/2023.07.24.550416","type":"posted-content","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T02:10:14Z","timestamp":1690251014000},"source":"Crossref","is-referenced-by-count":3,"title":["Mutation in F-actin Polymerization Factor Suppresses Distal Arthrogryposis Type 5 (DA5) PIEZO2 Pathogenic Variant in\n                  <i>Caenorhabditis elegans<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8179-8162","authenticated-orcid":false,"given":"Xiaofei","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3517-5973","authenticated-orcid":false,"given":"Harold E.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-7592","authenticated-orcid":false,"given":"Luis O","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9797-6402","authenticated-orcid":false,"given":"Briar","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-1534","authenticated-orcid":false,"given":"Valeria","family":"V\u00e1squez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8599-2031","authenticated-orcid":false,"given":"Andy","family":"Golden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023072611501169000_2023.07.24.550416v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25453"},{"key":"2023072611501169000_2023.07.24.550416v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1505-8"},{"key":"2023072611501169000_2023.07.24.550416v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctm.2017.01.001"},{"key":"2023072611501169000_2023.07.24.550416v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-422253"},{"key":"2023072611501169000_2023.07.24.550416v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2899"},{"key":"2023072611501169000_2023.07.24.550416v1.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-786004"},{"key":"2023072611501169000_2023.07.24.550416v1.7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-482489"},{"key":"2023072611501169000_2023.07.24.550416v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9085"},{"key":"2023072611501169000_2023.07.24.550416v1.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1602812"},{"key":"2023072611501169000_2023.07.24.550416v1.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221400110"},{"key":"2023072611501169000_2023.07.24.550416v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.add3598"},{"key":"2023072611501169000_2023.07.24.550416v1.12","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313348"},{"key":"2023072611501169000_2023.07.24.550416v1.13","doi-asserted-by":"publisher","DOI":"10.3390\/jdb7010006"},{"key":"2023072611501169000_2023.07.24.550416v1.14","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E20-04-0236"},{"key":"2023072611501169000_2023.07.24.550416v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/cm.21633"},{"key":"2023072611501169000_2023.07.24.550416v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2010.11.005"},{"key":"2023072611501169000_2023.07.24.550416v1.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003271"},{"key":"2023072611501169000_2023.07.24.550416v1.18","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.53603"},{"key":"2023072611501169000_2023.07.24.550416v1.19","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202112960"},{"key":"2023072611501169000_2023.07.24.550416v1.20","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.117.300179"},{"key":"2023072611501169000_2023.07.24.550416v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.09.023"},{"key":"2023072611501169000_2023.07.24.550416v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.07.024"},{"key":"2023072611501169000_2023.07.24.550416v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"2023072611501169000_2023.07.24.550416v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"2023072611501169000_2023.07.24.550416v1.25","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129635"},{"key":"2023072611501169000_2023.07.24.550416v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyab006"},{"key":"2023072611501169000_2023.07.24.550416v1.27","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E18-06-0347"},{"key":"2023072611501169000_2023.07.24.550416v1.28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1409233111"},{"key":"2023072611501169000_2023.07.24.550416v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/nature20793"},{"key":"2023072611501169000_2023.07.24.550416v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nature10801"},{"key":"2023072611501169000_2023.07.24.550416v1.31","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44706"},{"key":"2023072611501169000_2023.07.24.550416v1.32","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.132449"},{"key":"2023072611501169000_2023.07.24.550416v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0514-3"},{"key":"2023072611501169000_2023.07.24.550416v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16816-2"},{"key":"2023072611501169000_2023.07.24.550416v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36818-0"},{"key":"2023072611501169000_2023.07.24.550416v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.06.018"},{"key":"2023072611501169000_2023.07.24.550416v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