A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation

Abstract

Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development.

Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

“…We previously reported that a subtype of distal arthrogryposis type 5 (DA5) is caused by autosomal dominant mutations of PIEZO2 with slower inactivation kinetics than the wild-type channel 37 . Most patients with DA5 suffer from joint contractures and develop restrictive lung diseases 37,38 . Our data raise the possibility that overactivation of PIEZO2 + vagal neurons might overtly increase lung stretch responses in these patients and lead to respiratory complications.…”

Touch, Tension, and Transduction – The Function and Regulation of Piezo Ion Channels

“…Over a dozen mutations in Piezo2 are associated with several arthrogryposis disorders (Table 1) [39–41]. Two of these mutations have been electrophysiologically characterized and destabilize inactivation, leading to an overall increase of calcium influx [40].…”

Mammalian touch catches up

“…When Piezo2 was ablated in these cells using CRISPR/Cas9 technology, mechanically activated currents were abolished. Along with directly demonstrating that Piezo2 is necessary for mechanotransduction in human LTMRs, this study opens up new avenues for analyzing and genetically correcting, disease-causing Piezo2 mutations in human cell types [22,33,34]. …”