title: Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis.
abstract: Hereditary xerocytosis (HX, MIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis.
authors.affiliation: CancerCare Manitoba, Department of Hematology and Medical Oncology, Winnipeg, MB.
authors.forename: Ryan
authors.initials: R
authors.lastname: Zarychanski
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Schulz
authors.forename: Brett L
authors.initials: BL
authors.lastname: Houston
authors.forename: Yelena
authors.initials: Y
authors.lastname: Maksimova
authors.forename: Donald S
authors.initials: DS
authors.lastname: Houston
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.forename: Jesse
authors.initials: J
authors.lastname: Rinehart
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
mesh_terms: D000595:Amino Acid Sequence; D000745:Anemia, Hemolytic, Congenital / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004252:DNA Mutational Analysis; D041905:Erythroid Cells / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics* / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D040542:Mechanotransduction, Cellular / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D040901:Proteomics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human