title: Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis.
abstract: Hereditary xerocytosis (HX; MIM 194380) is an autosomal-dominant hemolytic anemia characterized by primary erythrocyte dehydration. In many patients, heterozygous mutations associated with delayed channel inactivation have been identified in PIEZO1. This report describes patients from 2 well-phenotyped HX kindreds, including from one of the first HX kindreds described, who lack predicted heterozygous PIEZO1-linked variants. Whole-exome sequencing identified novel, heterozygous mutations affecting the Gardos channel, encoded by the KCNN4 gene, in both kindreds. Segregation analyses confirmed transmission of the Gardos channel mutations with disease phenotype in affected individuals. The KCNN4 variants were different mutations in the same residue, which is highly conserved across species and within members of the small-intermediate family of calcium-activated potassium channel proteins. Both mutations were predicted to be deleterious by mutation effect algorithms. In sickle erythrocytes, the Gardos channel is activated under deoxy conditions, leading to cellular dehydration due to salt and water loss. The identification of KCNN4 mutations in HX patients supports recent studies that indicate it plays a critical role in normal erythrocyte deformation in the microcirculation and participates in maintenance of erythrocyte volume homeostasis.
authors.affiliation: Department of Pediatrics and.
authors.forename: Edyta
authors.initials: E
authors.lastname: Glogowska
authors.affiliation: Department of Pediatrics and.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lezon-Geyda
authors.affiliation: Department of Pediatrics and.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Maksimova
authors.affiliation: Department of Pediatrics and.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Schulz
authors.affiliation: Department of Pediatrics and Departments of Pathology and Genetics, Yale University School of Medicine, New Haven, CT.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000745:Anemia, Hemolytic, Congenital / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D007473:Ion Channels / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007473:Ion Channels; C496923:KCNN4 protein, human; C515204:PIEZO1 protein, human