Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis

Bertrand Coste, Gunnar Houge, Michael F. Murray, Nathan Stitziel, Michael Bandell, Monica A. Giovanni, Anthony Philippakis, Alexander Hoischen, Gunnar Riemer, Unni Steen, Vidar Martin Steen, Jayanti Mathur, James Cox, Matthew Lebo, Heidi Rehm, Scott T. Weiss, John N. Wood, Richard L. Maas, Shamil R. Sunyaev, Ardem Patapoutian

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


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 PIEZO2 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 PIEZO2 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 PIEZO2. We further show that overexpression of mutated PIEZO2 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.

Original languageEnglish
Pages (from-to)4667-4672
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 19 2013


  • Congenital contractures
  • Neuromuscular system
  • Whole exome sequencing
  • Whole genome sequencing


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