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

Andrea Delle Vedove, Markus Storbeck, Raoul Heller, Irmgard Hölker, Malavika Hebbar, Anju Shukla, Olafur Magnusson, Sebahattin Cirak, Katta M. Girisha, Mary O'Driscoll, Bart Loeys, Brunhilde Wirth

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1206-1216
Number of pages11
JournalAmerican Journal of Human Genetics
Volume99
Issue number5
DOIs
Publication statusPublished - 03-11-2016

Fingerprint

Arthrogryposis
Proprioception
Muscular Atrophy
Scoliosis
Libya
Exome
Phenotype
Afferent Neurons
Ophthalmoplegia
Frameshift Mutation
Mutation
Muscle Development
Pakistan
Touch
Contracture
Missense Mutation
Turkey
Oligonucleotide Array Sequence Analysis
Ion Channels
Respiratory Insufficiency

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Delle Vedove, Andrea ; Storbeck, Markus ; Heller, Raoul ; Hölker, Irmgard ; Hebbar, Malavika ; Shukla, Anju ; Magnusson, Olafur ; Cirak, Sebahattin ; Girisha, Katta M. ; O'Driscoll, Mary ; Loeys, Bart ; Wirth, Brunhilde. / Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 5. pp. 1206-1216.
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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.",
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Delle Vedove, A, Storbeck, M, Heller, R, Hölker, I, Hebbar, M, Shukla, A, Magnusson, O, Cirak, S, Girisha, KM, O'Driscoll, M, Loeys, B & Wirth, B 2016, 'Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis', American Journal of Human Genetics, vol. 99, no. 5, pp. 1206-1216. https://doi.org/10.1016/j.ajhg.2016.09.019

Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis. / Delle Vedove, Andrea; Storbeck, Markus; Heller, Raoul; Hölker, Irmgard; Hebbar, Malavika; Shukla, Anju; Magnusson, Olafur; Cirak, Sebahattin; Girisha, Katta M.; O'Driscoll, Mary; Loeys, Bart; Wirth, Brunhilde.

In: American Journal of Human Genetics, Vol. 99, No. 5, 03.11.2016, p. 1206-1216.

Research output: Contribution to journalArticle

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T1 - Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis

AU - Delle Vedove, Andrea

AU - Storbeck, Markus

AU - Heller, Raoul

AU - Hölker, Irmgard

AU - Hebbar, Malavika

AU - Shukla, Anju

AU - Magnusson, Olafur

AU - Cirak, Sebahattin

AU - Girisha, Katta M.

AU - O'Driscoll, Mary

AU - Loeys, Bart

AU - Wirth, Brunhilde

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