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

Nat Commun. 2015 Sep 21;6:8329. doi: 10.1038/ncomms9329.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anemia, Hemolytic, Congenital / genetics
  • Anemia, Hemolytic, Congenital / metabolism*
  • Child, Preschool
  • Erythrocytes / metabolism
  • Female
  • Genes, Recessive
  • Humans
  • Hydrops Fetalis / genetics
  • Hydrops Fetalis / metabolism*
  • Infant
  • Ion Channels / chemistry
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Lymphatic Diseases / genetics
  • Lymphatic Diseases / metabolism*
  • Male
  • Molecular Sequence Data
  • Mutation
  • Mutation, Missense
  • Sequence Alignment

Substances

  • Ion Channels
  • PIEZO1 protein, human

Supplementary concepts

  • Xerocytosis, hereditary