Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-09-21

AUTHORS

Viktor Lukacs, Jayanti Mathur, Rong Mao, Pinar Bayrak-Toydemir, Melinda Procter, Stuart M. Cahalan, Helen J. Kim, Michael Bandell, Nicola Longo, Ronald W. Day, David A. Stevenson, Ardem Patapoutian, Bryan L. Krock

ABSTRACT

Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema. More... »

PAGES

8329

Journal

TITLE

Nature Communications

ISSUE

1

VOLUME

6

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms9329

DOI

http://dx.doi.org/10.1038/ncomms9329

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1027046386

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26387913


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35 schema:description Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.
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43 PIEZO1 function
44 PIEZO1 loss
45 Piezo1
46 alleles
47 analysis
48 anemia
49 autosomal dominant haemolytic anaemia
50 autosomal recessive congenital lymphatic dysplasia
51 biallelic mutations
52 categories
53 cell types
54 cells
55 channels
56 clinical categories
57 congenital lymphatic dysplasia
58 consequences
59 dominant haemolytic anaemia
60 dysplasia
61 endothelium
62 erythrocytes
63 function
64 function mutations
65 haemolytic anaemia
66 hereditary lymphoedema
67 hereditary stomatocytosis
68 heterologous systems
69 humans
70 ion channels
71 loss
72 lymphatic dysplasia
73 lymphatic system
74 lymphoedema
75 mechanotransduction
76 mediator of mechanotransduction
77 mediators
78 mutations
79 novel autosomal recessive congenital lymphatic dysplasia
80 novel clinical category
81 novel role
82 pairs
83 pairs of siblings
84 patient's erythrocytes
85 patients
86 persistent lymphoedema
87 phenotypic consequences
88 recessive congenital lymphatic dysplasia
89 renal tubular cells
90 results
91 role
92 sequencing
93 siblings
94 stomatocytosis
95 study
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