title: Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis.
abstract: 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.
authors.affiliation: Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coste
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murray
authors.forename: Nathan
authors.initials: N
authors.lastname: Stitziel
authors.forename: Michael
authors.initials: M
authors.lastname: Bandell
authors.forename: Monica A
authors.initials: MA
authors.lastname: Giovanni
authors.forename: Anthony
authors.initials: A
authors.lastname: Philippakis
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Gunnar
authors.initials: G
authors.lastname: Riemer
authors.forename: Unni
authors.initials: U
authors.lastname: Steen
authors.forename: Vidar Martin
authors.initials: VM
authors.lastname: Steen
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.forename: Matthew
authors.initials: M
authors.lastname: Lebo
authors.forename: Heidi
authors.initials: H
authors.lastname: Rehm
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
mesh_terms: D000328:Adult; D001176:Arthrogryposis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000235:genetics*; D009154:Mutation
chemical_list: D007473:Ion Channels