Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Andolfo, Immacolata; Russo, Roberta; Manna, Francesco; Shmukler, Boris E.; Gambale, Antonella; Vitiello, Giuseppina; De Rosa, Gianluca; Brugnara, Carlo; Alper, Seth L.; Snyder, L. Michael; Iolascon, Achille
• Is Part Of: American journal of hematology. Volume 90:Issue 10(2015:Oct.)
• Page Start: 921
• Page End: 926
• Publication Date: 2015-10
• Subjects: Hematology -- Periodicals; 616.15
• DOI: 10.1002/ajh.24117
• Languages: English
• ISSNs: 0361-8609

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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, <italic>PIEZO1</italic>. A recent study has identified two families with DHSt associated with a single mutation in the <italic>KCNN4</italic> gene encoding the Gardos channel (KCa3.1), the erythroid Ca<sup>2+</sup>‐sensitive K<sup>+</sup> channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with <italic>KCNN4</italic> mutations, two previously undiagnosed DHSt families. Family NA exhibited the same <italic>de novo</italic> 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 <italic>KCNN4</italic> in the mutated patients and during erythroid differentiation of CD34+ cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development. Am. J. Hematol. 90:921–926, 2015. © 2015 Wiley Periodicals, Inc.</p> </abstract>