title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
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.
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Lukacs
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah 84108, USA.|Department of Pathology, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Mao
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah 84108, USA.|Department of Pathology, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah 84108, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Procter
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cahalan
authors.affiliation: Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Helen J
authors.identifier: http://orcid.org/0000-0003-0096-7740
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bandell
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Day
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah 84112, USA.|Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, California 94305, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stevenson
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah 84108, USA.|Department of Pathology, University of Utah, Salt Lake City, Utah 84112, USA.|Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Krock
mesh_terms: D000595:Amino Acid Sequence; D000745:Anemia, Hemolytic, Congenital / Q000235:genetics / Q000378:metabolism*; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics / Q000378:metabolism*; D007223:Infant; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008206:Lymphatic Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D016415:Sequence Alignment
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human