{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:10:11Z","timestamp":1793286611633,"version":"4.5.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,3,19]]},"abstract":"<jats:p>\n                    Mechanotransduction, the pathway by which mechanical forces are translated to biological signals, plays important but poorly characterized roles in physiology. PIEZOs are recently identified, widely expressed, mechanically activated ion channels that are hypothesized to play a role in mechanotransduction in mammals. Here, we describe two distinct\n                    <jats:italic>PIEZO2<\/jats:italic>\n                    mutations in patients with a subtype of Distal Arthrogryposis Type 5 characterized by generalized autosomal dominant contractures with limited eye movements, restrictive lung disease, and variable absence of cruciate knee ligaments. Electrophysiological studies reveal that the two\n                    <jats:italic>PIEZO2<\/jats:italic>\n                    mutations affect biophysical properties related to channel inactivation: both E2727del and I802F mutations cause the PIEZO2-dependent, mechanically activated currents to recover faster from inactivation, while E2727del also causes a slowing of inactivation. Both types of changes in kinetics result in increased channel activity in response to a given mechanical stimulus, suggesting that Distal Arthrogryposis Type 5 can be caused by gain-of-function mutations in\n                    <jats:italic>PIEZO2<\/jats:italic>\n                    . We further show that overexpression of mutated\n                    <jats:italic>PIEZO2<\/jats:italic>\n                    cDNAs does not cause constitutive activity or toxicity to cells, indicating that the observed phenotype is likely due to a mechanotransduction defect. Our studies identify a type of channelopathy and link the dysfunction of mechanically activated ion channels to developmental malformations and joint contractures.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1221400110","type":"journal-article","created":{"date-parts":[[2013,3,5]],"date-time":"2013-03-05T06:32:33Z","timestamp":1362465153000},"page":"4667-4672","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":236,"title":["Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis"],"prefix":"10.1073","volume":"110","author":[{"given":"Bertrand","family":"Coste","sequence":"first","affiliation":[{"name":"Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Houge","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway;"},{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Murray","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Stitziel","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bandell","sequence":"additional","affiliation":[{"name":"Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica A.","family":"Giovanni","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Philippakis","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hoischen","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway;"},{"name":"Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Riemer","sequence":"additional","affiliation":[{"name":"TRS National Resource Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, 1450 Nesoddtangen, Norway;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unni","family":"Steen","sequence":"additional","affiliation":[{"name":"TRS National Resource Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, 1450 Nesoddtangen, Norway;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidar Martin","family":"Steen","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway;"},{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayanti","family":"Mathur","sequence":"additional","affiliation":[{"name":"Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Cox","sequence":"additional","affiliation":[{"name":"Molecular Nociception Group, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lebo","sequence":"additional","affiliation":[{"name":"Partners Center for Personalized Genetic Medicine, Partners HealthCare, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Rehm","sequence":"additional","affiliation":[{"name":"Partners Center for Personalized Genetic Medicine, Partners HealthCare, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott T.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Partners Center for Personalized Genetic Medicine, Partners HealthCare, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John N.","family":"Wood","sequence":"additional","affiliation":[{"name":"Molecular Nociception Group, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Maas","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamil R.","family":"Sunyaev","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ardem","family":"Patapoutian","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037;"},{"name":"Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,3,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(39)80012-9"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.I.00281"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/01202412-199707000-00002"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19961111)65:4<282::AID-AJMG7>3.0.CO;2-R"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30289"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32668"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320110208"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.30.1.78"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31648"},{"key":"e_1_3_3_10_2","article-title":"The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis","author":"Dieterich K","year":"2012","unstructured":"K Dieterich, et al., The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. Hum Mol Genet, 10.1093\/hmg\/dds514. (2012).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.11.014"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp587"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6899com"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1086\/368294"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1193270"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10801"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-422253"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10812"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.07.014"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.04.012"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00042.2009"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2597"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4521-09.2010"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.29.20450"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.knee.2008.08.004"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0387-7604(98)00037-0"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07517"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq330"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.1.308"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.581"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.712"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1221400110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T22:25:55Z","timestamp":1649802355000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1221400110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3,4]]},"references-count":34,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,3,19]]}},"alternative-id":["10.1073\/pnas.1221400110"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1221400110","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3,4]]},"assertion":[{"value":"2013-03-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}