Hereditary xerocytosis, a misleading anemia

Barreto, Roberta; Arrizabalaga, Beatriz; Rastrollo, A. B. De la Hoz; Garcı́a-Orad, Africa; Vallejo, I; Bento, Celeste; Villegas, Ana; García‐Ruiz, Juan Carlos

doi:10.1007/s00277-016-2716-9

Cited by 12 publications

(6 citation statements)

References 6 publications

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“…The dyserythropoietic features detected in the bone marrow of II.4 supports the hypothesis that KCNN4 may play a role in erythroid maturation, suggested also by the I-V-curves in precursor cells indicating a higher abundance of Gardos channels in erythroid precursors compared to mature RBCs; therefore, iron overload detected in our and other patients with KCNN4 mutation 11 may be a consequence of dyserythropoiesis, similar to what is reported in DHSt with PIEZO1 mutations 28, 29 . The history of the patients reported here confirms that congenital hemolytic anemia due to abnormal cation permeability may represent a diagnostic challenge that is now overcome by means of the new Next Generation Sequencing technology approaches.…”

Section: Discussionsupporting

confidence: 89%

‘Gardos Channelopathy’: a variant of hereditary Stomatocytosis with complex molecular regulation

Fermo

Bogdanova

Petkova-Kirova

et al. 2017

Sci Rep

104

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The Gardos channel is a Ca2+ sensitive, K+ selective channel present in several tissues including RBCs, where it is involved in cell volume regulation. Recently, mutations at two different aminoacid residues in KCNN4 have been reported in patients with hereditary xerocytosis. We identified by whole exome sequencing a new family with two members affected by chronic hemolytic anemia carrying mutation R352H in the KCNN4 gene. No additional mutations in genes encoding for RBCs cytoskeletal, membrane or channel proteins were detected. We performed functional studies on patients’ RBCs to evaluate the effects of R352H mutation on the cellular properties and eventually on the clinical phenotype. Gardos channel hyperactivation was demonstrated in circulating erythrocytes and erythroblasts differentiated ex-vivo from peripheral CD34+ cells. Pathological alterations in the function of multiple ion transport systems were observed, suggesting the presence of compensatory effects ultimately preventing cellular dehydration in patient’s RBCs; moreover, flow cytometry and confocal fluorescence live-cell imaging showed Ca2+ overload in the RBCs of both patients and hypersensitivity of Ca2+ uptake by RBCs to swelling. Altogether these findings suggest that the ‘Gardos channelopathy’ is a complex pathology, to some extent different from the common hereditary xerocytosis.

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Section: Discussionsupporting

confidence: 89%

‘Gardos Channelopathy’: a variant of hereditary Stomatocytosis with complex molecular regulation

Fermo

Bogdanova

Petkova-Kirova

et al. 2017

Sci Rep

104

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“…The candidate gene locus was first localized at 16q23–24 . Several years later, PIEZO1, a cation selective channel activated by mechanical force, was identified as the causative gene of both isolated and syndromic forms of DHS by exome sequencing . We herein classified the nonsyndromic form of DHS PIEZO1‐related as DHS type 1b (DHS1b).…”

Section: Hereditary Stomatocytosis: Syndromic and Nonsyndromic Formsmentioning

confidence: 99%

Hereditary stomatocytosis: An underdiagnosed condition

et al. 2017

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Hereditary stomatocytoses are a wide class of hemolytic anemias characterized by alterations of ionic flux with increased cation permeability that results in inappropriate shrinkage or swelling of the erythrocytes, and water lost or gained osmotically. The last few years have been crucial for new acquisitions in this field in terms of identifying new causative genes and of studying their pathogenetic mechanisms. This review summarizes the main features of erythrocyte membrane transport diseases, dividing them into forms with either isolated erythroid phenotype (nonsyndromic) or extra-hematological manifestations (syndromic), and focusing particularly on the most recent advances regarding dehydrated forms of hereditary stomatocytosis and familial pseudohyperkalemia.

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“…A recent case report suggests that the c.7505A>G variant (dbSNP: rs34830861) can cause a DHS phenotype (Del Orbe Barreto et al . ). Although the patient showed an abnormal curve shifted to the left on ektacytometry, and other blood findings supported the diagnosis of DHS, the rs34830861 SNP has been reported in 97 heterozygous cases in ExAC.…”

Section: Introductionmentioning

confidence: 97%

Human phenotypes caused by PIEZO1 mutations; one gene, two overlapping phenotypes?

Martin-Almedina

Mansour

Østergaard

2018

The Journal of Physiology

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PIEZO1 is a large mechanosensitive ion channel protein. Diseases associated with PIEZO1 include autosomal recessive generalised lymphatic dysplasia of Fotiou (GLDF) and autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal oedema (DHS). The two disorders show overlapping features, fetal hydrops/perinatal oedema have been reported in both. Electrophysiological studies suggest opposite mechanisms of action: the mutations identified in GLDF patients cause a loss-of-function mechanism of disease and mutations in DHS patients cause gain of function. This raises the question: Is the pathogenic disease mechanism behind the fetal oedema the same in the two phenotypes? In this Symposium Review, we will discuss the two conditions and highlight key questions that remain to be answered. For instance, the perinatal oedema often resolves soon after birth and we are still at a loss to understand why. Are there any mechanisms which could compensate for the faulty PIEZO1 in these patients? Are there physiological changes at birth that are less reliant on the function of PIEZO1? Thus, there is a clear need for further studies into the two disorders, in order to fully understand the role of PIEZO1 in health and disease.

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Hereditary xerocytosis, a misleading anemia

Cited by 12 publications

References 6 publications

‘Gardos Channelopathy’: a variant of hereditary Stomatocytosis with complex molecular regulation

‘Gardos Channelopathy’: a variant of hereditary Stomatocytosis with complex molecular regulation

Hereditary stomatocytosis: An underdiagnosed condition

Human phenotypes caused by PIEZO1 mutations; one gene, two overlapping phenotypes?

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