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.
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