Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis

Abstract

We report ten individuals of four independent consanguineous families from Turkey, India, Libya, and Pakistan with a variable clinical phenotype that comprises arthrogryposis, spontaneously resolving respiratory insufficiency at birth, muscular atrophy predominantly of the distal lower limbs, scoliosis, and mild distal sensory involvement. Using whole-exome sequencing, SNPchip-based linkage analysis, DNA microarray, and Sanger sequencing, we identified three independent homozygous frameshift mutations and a homozygous deletion of two exons in PIEZO2 that segregated in all affected individuals of the respective family. The mutations are localized in the N-terminal and central region of the gene, leading to nonsense-mediated transcript decay and consequently to lack of PIEZO2 protein. In contrast, heterozygous gain-of-function missense mutations, mainly localized at the C terminus, cause dominant distal arthrogryposis 3 (DA3), distal arthrogryposis 5 (DA5), or Marden-Walker syndrome (MWKS), which encompass contractures of hands and feet, scoliosis, ophthalmoplegia, and ptosis. PIEZO2 encodes a mechanosensitive ion channel that plays a major role in light-touch mechanosensation and has recently been identified as the principal mechanotransduction channel for proprioception. Mice ubiquitously depleted of PIEZO2 are postnatally lethal. However, individuals lacking PIEZO2 develop a not life-threatening, slowly progressive disorder, which is likely due to loss of PIEZO2 protein in afferent neurons leading to disturbed proprioception causing aberrant muscle development and function. Here we report a recessively inherited PIEZO2-related disease and demonstrate that depending on the type of mutation and the mode of inheritance, PIEZO2 causes clinically distinguishable phenotypes.

Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

“…Our mouse genetics data demonstrate that Piezo2 is a versatile mechanotransducer, functioning as a sensor of lung inflation in addition to touch and proprioception 15,17 . Recently, humans carrying compound inactivating variants of PIEZO2 were reported to have selective loss of discriminative touch perception and profoundly decreased proprioception; these individuals also exhibited shallow breathing during infancy 35,36 . Thus, the general role of Piezo2 in somatosensory mechanotransduction is conserved between mice and humans.…”

Distal Arthrogryposis with Impaired Proprioception and Touch: Description of an Early Phenotype in a Boy with Compound Heterozygosity of PIEZO2 Mutations and Review of the Literature

“…Distal arthrogryposis in patients with DAIPT has been observed as "congenital," particularly regarding bilateral foot deformities [Delle Vedove et al, 2016]. Contracture deformities of the upper limbs were present in 15 of the 16 previously reported patients.…”

“…Cognitive development was usually normal. Only in one family, mild cognitive disability had been described in 2 affected children, possibly influenced also by a low socioeconomic status of the family [Delle Vedove et al, 2016]. Heterozygous carriers of PIEZO2 loss-of-function mutations (parents and siblings) were healthy, without any signs of neuromuscular or skeletal symptomatology.…”

“…The majority of PIEZO2 dominant mutations are clustered in 2 regions of the gene that encode the C-terminal domain and appear to be mutation hotspots, particularly the last exon 52. In contrast, the mutations in recessive DAIPT do not show any locus predilection, as they are distributed throughout the entire gene [Chesler et al, 2016;Delle Vedove et al, 2016;Haliloglu et al, 2017;Mahmud et al, 2017]. The PIEZO2 protein contains more than 30 transmembrane domains and functions as part of mechanically activated cation channels [Coste et al, 2010].…”

Genetics of neuromuscular fetal akinesia in the genomics era

“…Although Piezo2 knockout is perinatal lethal in mice, human life expectancy is normal. It has been suggested that humans with homozygous loss-of-function alleles may produce some functional PIEZO2 through alternative splicing 44. This may explain the relatively mild phenotype compared with mice.…”