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

Abstract

Key Points Dehydrated hereditary stomatocytosis is characterized by abnormal RBC morphology but may involve pseudohyperkalemia and perinatal edema. This syndrome is associated with germline mutations in PIEZO1, encoding a transmembrane protein that induces mechanosensitive currents.

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

“…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].…”

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

“…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].…”

Hereditary xerocytosis, a misleading anemia

“…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].…”