title: 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.
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Delle Vedove
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Storbeck
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Hölker
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka 576104, India.
authors.forename: Malavika
authors.initials: M
authors.lastname: Hebbar
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka 576104, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Shukla
authors.affiliation: deCODE genetics, 101 Reykjavik, Iceland.
authors.forename: Olafur
authors.initials: O
authors.lastname: Magnusson
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Children's Hospital, University Hospital of Cologne, 50931 Cologne, Germany.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka 576104, India.
authors.forename: Katta M
authors.initials: KM
authors.lastname: Girisha
authors.affiliation: Birmingham Women's NHS Foundation Trust, Birmingham T15 2TH, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Driscoll
authors.affiliation: Antwerp University Hospital, 2650 Edegem, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Electronic address: brunhilde.wirth@uk-koeln.de.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D054119:Arachnodactyly / Q000175:diagnosis / Q000235:genetics; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D016569:Blepharophimosis / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003240:Connective Tissue Diseases / Q000175:diagnosis / Q000235:genetics; D003286:Contracture / Q000175:diagnosis / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D007194:India; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008002:Libya; D008297:Male; D040542:Mechanotransduction, Cellular; D009133:Muscular Atrophy / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D009886:Ophthalmoplegia / Q000175:diagnosis / Q000235:genetics; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011434:Proprioception; D012127:Respiratory Distress Syndrome, Newborn / Q000175:diagnosis / Q000235:genetics*; D012600:Scoliosis / Q000175:diagnosis / Q000235:genetics*; D014421:Turkey; D055815:Young Adult
chemical_list: D007473:Ion Channels; C000589132:PIEZO2 protein, human