PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus

Imashuku, Shinsaku; Muramatsu, Hideki; Sugihara, Takashi; Wang, Xinan; Yoshida, Kenichi; Kato, Ayako; Kato, Koichi; Tatsumi, Yasuaki; Hattori, Ai; Kita, Shinya; Oe, Keishi; Sueyoshi, Atsushi; Usui, Takeshi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji; Kanno, Hitoshi

doi:10.1007/s12185-016-1970-x

Cited by 23 publications

(35 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…The mutation was already reported in 8 unrelated cases described by Albuisson et al [11] and very recently in a Japanese family [17] (Table 2). Although being also detected in 2 of 600 healthy French controls, this mutation was considered pathogenic; in fact, patch-clamp experiments in transfected HEK293 cells demonstrated a considerable increase in the inactivation time in the mutant compared to wild-type channel kinetics, indicating that it represents a gain-of-function mutation [11].…”

Section: Discussionmentioning

confidence: 73%

“…Patient AII.1 displayed two DVT episodes 5 and 33 years after splenectomy, and patient BII.1 had pulmonary embolism 20 years after surgery. It is worth mentioning that the only patient reported in the literature without thromboembolic complication after splenectomy had a relatively short follow-up [17]. …”

Section: Discussionmentioning

confidence: 99%

“…An important factor in this regard may be dyserythropoiesis, which was also present in patient BII.1. The occurrence of dyserythropoiesis has been documented in a variant of hereditary stomatocytosis due to Gly796Arg mutation of the erythroid anion exchanger [24] and in one case with HX associated with hereditary high phosphatidylcholine haemolytic anaemia [17] but excluded in another PIEZO1 mutated patient described by Archer et al [14]. …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hereditary Xerocytosis due to Mutations inPIEZO1Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families

Fermo

Vercellati

Marcello

et al. 2017

Case Reports in Hematology

View full text Add to dashboard Cite

Hereditary xerocytosis (HX) is a rare disorder caused by defects of RBC permeability, associated with haemolytic anaemia of variable degree and iron overload. It is sometimes misdiagnosed as hereditary spherocytosis or other congenital haemolytic anaemia. Splenectomy is contraindicated due to increased risk of thromboembolic complications. We report the clinical, haematological, and molecular characteristics of four patients from two unrelated Italian families affected by HX, associated with beta-thalassemia trait and heterozygous pyruvate kinase deficiency, respectively. Two patients had been splenectomised and displayed thrombotic episodes. All patients had iron overload in the absence of transfusion, two of them requiring iron chelation. The diagnosis of HX was confirmed by LoRRca Osmoscan analysis showing a left-shifted curve. PIEZO1 gene sequencing revealed the presence of mutation p.E2496ELE, showing that this is one of the most frequent mutations in this disease. The concomitant defects did not aggravate the clinical phenotype; however, in one patient, the initial diagnosis of pyruvate kinase deficiency delayed the correct diagnosis of HX for many years and resulted in splenectomy followed by thrombotic complications. The study underlines the importance of a precise diagnosis in HX, particularly in view of splenectomy, and the need of a molecular confirmation of suspected RBC enzymopathy.

show abstract

“…Hereditary diseases with ineffective erythropoiesis such as thalassemia syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and hereditary xerocytosis/dehydrated hereditary stomatocytosis also manifest as systemic iron overload due to downregulation of hepcidin expression, and they may need to be differentiated from HH in clinical settings (Table 1) [51,53,[109][110][111].…”

Section: Hereditary Disorders That Should Be Differentiated From Hhmentioning

confidence: 99%

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Kawabata

2017

Int J Hematol

View full text Add to dashboard Cite

Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

show abstract

PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus

Cited by 23 publications

References 16 publications

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

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

Hereditary Xerocytosis due to Mutations inPIEZO1Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Contact Info

Product

Resources

About