title: Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis).
abstract: Dehydrated hereditary stomatocytosis (DHSt) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated MCHC and MCV, and decreased osmotic fragility. The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1. A recent study has identified two families with DHSt associated with a single mutation in the KCNN4 gene encoding the Gardos channel (KCa3.1), the erythroid Ca(2+) -sensitive K(+) channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with KCNN4 mutations, two previously undiagnosed DHSt families. Family NA exhibited the same de novo missense mutation as that recently described, suggesting a hot spot codon for DHSt mutations. Family WO carried a novel, inherited missense mutation in the ion transport domain of the channel. The patients' mild hemolytic anemia did not improve post-splenectomy, but splenectomy led to no serious thromboembolic events. We further characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of CD34+ cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development.
authors.affiliation: Department Of Molecular Medicine And Medical Biotechnologies, "Federico II" University Of Naples, Naples, Italy.|Biotecnologie Avanzate, CEINGE, Naples, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Andolfo
authors.affiliation: Department Of Molecular Medicine And Medical Biotechnologies, "Federico II" University Of Naples, Naples, Italy.|Biotecnologie Avanzate, CEINGE, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department Of Molecular Medicine And Medical Biotechnologies, "Federico II" University Of Naples, Naples, Italy.|Biotecnologie Avanzate, CEINGE, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Manna
authors.affiliation: Renal Division And Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Department Of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.affiliation: Department Of Molecular Medicine And Medical Biotechnologies, "Federico II" University Of Naples, Naples, Italy.|Biotecnologie Avanzate, CEINGE, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Gambale
authors.affiliation: Biotecnologie Avanzate, CEINGE, Naples, Italy.|Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Viale Oxford, Rome, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Vitiello
authors.affiliation: Department Of Molecular Medicine And Medical Biotechnologies, "Federico II" University Of Naples, Naples, Italy.|Biotecnologie Avanzate, CEINGE, Naples, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Rosa
authors.affiliation: Department Of Laboratory Medicine, Boston Children's Hospital And Department Of Pathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.affiliation: Renal Division And Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.affiliation: Dept Of Hospital Laboratories, University Of Massachusetts Medical Center, Worcester, MA.|Quest Diagnositics, LLC MA, Marlborough, Massachusetts.
authors.forename: L Michael
authors.initials: LM
authors.lastname: Snyder
authors.affiliation: Department Of Molecular Medicine And Medical Biotechnologies, "Federico II" University Of Naples, Naples, Italy.|Biotecnologie Avanzate, CEINGE, Naples, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
mesh_terms: D000293:Adolescent; D000328:Adult; D000745:Anemia, Hemolytic, Congenital / Q000235:genetics* / Q000601:surgery; D000818:Animals; D005260:Female; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics* / Q000601:surgery; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D020014:K562 Cells; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D013156:Splenectomy / Q000009:adverse effects; D013923:Thromboembolism / Q000209:etiology / Q000235:genetics
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human