Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1

Andolfo, Immacolata; Alper, Seth L.; Franceschi, Lucia De; Auriemma, Carla; Russo, Roberta; Falco, Luigia De; Vallefuoco, Fara; Esposito, Maria Rosaria; Vandorpe, David H.; Shmukler, Boris E.; Narayan, Rupa; Montanaro, Donatella; D’Armiento, Maria; Vetro, Annalisa; Limongelli, Ivan; Zuffardi, Orsetta; Glader, Bertil; Schrier, Stanley L.; Brugnara, Carlo; Stewart, Gordon W.; Delaunay, Jean; Iolascon, Achille

doi:10.1182/blood-2013-02-482489

Cited by 260 publications

(333 citation statements)

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“…Mutations in several genes have been shown to cause red cell cation leak disorders. These include chloride-bicarbonate exchanger SLC4A1/AE1/ Band 3 in CHC and in atypical forms of hereditary spherostomatocytosis [23,24], ammonia transporter RHAG (Rh-associated glycoprotein) in isolated stomatin-deficient OHSt [25,26], glucose transporter GLUT1 in echinocytosis with paroxysmal dyskinesia [27], stomatin-deficient CHC [28] or in CHC [29] or pseudohyperkalemia and hemolysis [30] with neurological symptoms, and PIEZO1 (mechanosensitive cation channel protein FAM38A) in DHSt [10][11][12][13]. A recent study has highlighted a novel DHSt gene, KCNN4, encoding the widely expressed KCa3.1 Gardos channel, a Ca 21 -sensitive K 1 channel of intermediate conductance [14].…”

Section: Discussionmentioning

confidence: 99%

“…C57BL6/J mouse embryonic tissues were collected at E9.5, E10.5, E12.5, E15.5 as previously described [11].…”

Section: Methodsmentioning

confidence: 99%

“…Several functional characterizations of identified PIEZO1 mutations in DHSt families have uniformly demonstrated gain-of-function properties consistent with the increased net ion fluxes leading to DHSt [7,[10][11][12][13].…”

Section: Introductionmentioning

confidence: 90%

“…The causative gene of the condition was recently identified in the FAM38A gene encoding the mechanosensitive cation channel, PIEZO1 [10,11]. Several functional characterizations of identified PIEZO1 mutations in DHSt families have uniformly demonstrated gain-of-function properties consistent with the increased net ion fluxes leading to DHSt [7,[10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

et al. 2015

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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 21 -sensitive K 1 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 CD341 cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development.

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Section: Discussionmentioning

confidence: 99%

“…C57BL6/J mouse embryonic tissues were collected at E9.5, E10.5, E12.5, E15.5 as previously described [11].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

et al. 2015

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“…Hereditary Xerocytosis (HX), formally known as hereditary dehydrated stomatocytosis, is an autosomal dominant congenital hemolytic anemia associated with a leak of intracellular potassium usually accompanied by increased mean corpuscular hemoglobin (Hb) concentration [1]. Gain-of-function mutations in PIEZO1, encoding a mechanosensitive cation channel, and deleterious mutations of KCNN4, encoding the Gardos channel have been implicated in its pathogenicity [2].…”

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confidence: 99%