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.