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

Am J Hum Genet. 2016 Nov 3;99(5):1206-1216. doi: 10.1016/j.ajhg.2016.09.019. Epub 2016 Oct 27.


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.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics
  • Adolescent
  • Adult
  • Alleles
  • Arachnodactyly / diagnosis
  • Arachnodactyly / genetics
  • Arthrogryposis / diagnosis
  • Arthrogryposis / genetics*
  • Blepharophimosis / diagnosis
  • Blepharophimosis / genetics
  • Child
  • Child, Preschool
  • Connective Tissue Diseases / diagnosis
  • Connective Tissue Diseases / genetics
  • Contracture / diagnosis
  • Contracture / genetics
  • Female
  • Genome-Wide Association Study
  • Homozygote
  • Humans
  • India
  • Ion Channels / genetics*
  • Ion Channels / metabolism
  • Libya
  • Male
  • Mechanotransduction, Cellular
  • Muscular Atrophy / diagnosis
  • Muscular Atrophy / genetics*
  • Mutation, Missense
  • Ophthalmoplegia / diagnosis
  • Ophthalmoplegia / genetics
  • Pakistan
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Proprioception*
  • Respiratory Distress Syndrome, Newborn / diagnosis
  • Respiratory Distress Syndrome, Newborn / genetics*
  • Scoliosis / diagnosis
  • Scoliosis / genetics*
  • Turkey
  • Young Adult


  • Ion Channels
  • PIEZO2 protein, human

Supplementary concepts

  • Marden-Walker syndrome