Delle Vedove, Andrea, Storbeck, Markus, Heller, Raoul, Hoelker, Irmgard, Hebbar, Malavika, Shulda, Anju, Magnusson, Olafur, Cirak, Sebahattin, Girisha, Katta M., O'Driscoll, Mary, Loeys, Bart ORCID: 0000-0003-3703-9518 and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2016). Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis. Am. J. Hum. Genet., 99 (5). S. 1206 - 1217. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Delle Vedove, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Storbeck, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heller, RaoulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelker, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hebbar, MalavikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shulda, AnjuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Magnusson, OlafurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Girisha, Katta M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Driscoll, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeys, BartUNSPECIFIEDorcid.org/0000-0003-3703-9518UNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
URN: urn:nbn:de:hbz:38-255972
DOI: 10.1016/j.ajhg.2016.09.019
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 99
Number: 5
Page Range: S. 1206 - 1217
Date: 2016
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MARDEN-WALKER-SYNDROME; DISTAL ARTHROGRYPOSIS; 5-SPLICE-SITE RECOGNITION; MUTATIONS; CHANNELS; MECHANOTRANSDUCTION; GENE; PHENOTYPES; MECHANISM; PROTEINSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25597

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