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 language | English |
|---|---|
| Pages (from-to) | 1206-1216 |
| Number of pages | 11 |
| Journal | American Journal of Human Genetics |
| Volume | 99 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 03-11-2016 |
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All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)
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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 journal › Article
TY - JOUR
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
PY - 2016/11/3
Y1 - 2016/11/3
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2016.09.019
DO - 10.1016/j.ajhg.2016.09.019
M3 - Article
VL - 99
SP - 1206
EP - 1216
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -