Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene

Abstract

PIEZO2 protein is a unique ion channel that converts mechanical impulses into cellular signals in somatosensory neurons and is involved in various mechanotransduction pathways. The recessive PIEZO2 loss-of-function pathogenic variants are associated with distal arthrogryposis with impaired proprioception and touch (DAIPT). Here we present three new DAIPT patients. The genetic diagnosis was established by exome sequencing and let us to identify 6 novel loss-of-function PIEZO2 variants: four splicing (c.1080+1G>A, c.4092+1G>T, c.6355+1G>T, and c.7613+1G>A), one nonsense (c.6088C>T) and one frameshift variant (c.6175_6191del) for which mosaic variant was identified in proband's mother. All patients presented typical symptoms at birth, with congenital contractures, bilateral hip dislocation/dysplasia, generalized hypotonia, transient feeding and difficulties. Two were afflicted by transient respiratory insufficiency. In all children motor development was severely delayed. In one patient, severe cognitive delay was also observed. Moreover, among the cases described by us there is the youngest diagnosed child to date.

Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception

“…While Piezo2 expression is also reported in the urothelium ( 23 ), the expression and localization of PIEZO2 protein in the urinary tract is unknown. Intriguingly, patients deficient in PIEZO2 expression exhibit voiding dysfunction ( 23 ), although this may not be the case for all patients ( 24 ). In addition, mouse LUT function is also reportedly dependent on Piezo2 expression in sensory neurons and possibly the urothelium ( 23 ); however, whether Piezo2 expression is critical for urothelial mechanotransduction, whether urothelial expressed PIEZO channels regulate voiding behavior, and whether PIEZO1 and PIEZO2 act in a coordinate fashion to regulate these events remain unknown.…”

PIEZO2‐related distal arthrogryposis type 5: Longitudinal follow‐up of a three‐generation family broadens phenotypic spectrum, complications, and health surveillance recommendations for this patient group

“…PIEZO2 has been shown to play a role in several mechanotransduction processes including proprioception, detection of light touch and detection of noxious mechanical stimuli and is predominantly found in sensory tissue such as the dorsal root ganglia sensory neurons and Merkel cells (Wu, Lewis, & Grandl, 2017). Inactivating variants in PIEZO2 were identified in patients with mechanosensory deficiencies resulting in associated ataxia and dysmetria (Chesler et al, 2016), biallelic loss of function mutations have subsequently been associated with an arthrogryposis syndrome with contractures, scoliosis, and proprioception defects (Delle Vedove et al, 2016; Haliloglu et al, 2017; Klaniewska et al, 2021; Mahmud et al, 2017; Yamaguchi et al, 2019). To date, these inactivating variants are distributed mainly in the N‐terminal region (Ma, Zhao, Cai, & Hao, 2019).…”

Mechanosensitive PIEZO2 channels shape coronary artery development

“…Ever since the discovery of mechanosensitive PIEZO channels 21 , PIEZO2 has been primarily characterized as a sensory ion channel, present in a variety of sensory neuron types, the function of which is to sense mechanical forces important for touch, interoception and pain [30][31][32][33][34] . Importantly, PIEZO2 pathogenic variants are associated with congenital disorders in humans, including joint, craniofacial, brain, and cardiovascular defects [35][36][37][38][39][40][41][42] . However, the precise function of mechanosensitive PIEZO2 channels in non-sensory cells, including endothelial cells, remains largely unstudied.…”