Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

Andolfo, Immacolata; Martone, Stefania; Rosato, Barbara Eleni; Marra, Roberta; Gambale, Antonella; Forni, Gian Luca; Pinto, Valeria; Göransson, Magnus; Papadopoulou, Vasiliki; Gavillet, Mathilde; Elalfy, Mohsen Saleh; Panarelli, Antonella; Tomaiuolo, Giovanna; Iolascon, Achille; Russo, Roberta

doi:10.3390/genes12070958

Cited by 30 publications

(44 citation statements)

References 27 publications

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“…The only new and most likely important pathogenic mutations of the SPTB gene (p.C183Y) were detected within the panel of 71 genes recommended for RBC pathologies by Russo et al (Table 2; for details, see Additional File S1, Table S3, and Additional File S2) [22] and confirmed via Sanger sequencing of gDNA and cDNA (Additional File S1 and Section 4). Thirteen new variants were detected in the genes included in this panel, of which only four were present in both patients (including the above-mentioned SPTB gene muta-tion).…”

Section: Wes Results Analysismentioning

confidence: 88%

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Identification of a Novel Mutation of β-Spectrin in Hereditary Spherocytosis Using Whole Exome Sequencing

Bogusławska

Skulski

Machnicka

et al. 2021

IJMS

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Hereditary spherocytosis (HS), the most commonly inherited hemolytic anemia in northern Europeans, comprises a group of diseases whose heterogeneous genetic basis results in a variable clinical presentation. High-throughput genome sequencing methods have made a leading contribution to the recent progress in research on and diagnostics of inherited diseases and inspired us to apply whole exome sequencing (WES) to identify potential mutations in HS. The data presented here reveal a novel mutation probably responsible for HS in a single Polish family. Patients with clinical evidence of HS (clinical symptoms, hematological data, and EMA test) were enrolled in the study. The examination of the resulting WES data showed a number of polymorphisms in 71 genes associated with known erythrocyte pathologies (including membranopathies, enzymopathies, and hemoglobinopathies). Only a single SPTB gene variant indicated the possible molecular mechanism of the disease in the studied family. The new missense mutation p.C183Y was identified using WES in the SPTB gene, which is most likely the cause of clinical symptoms typical of hereditary spherocytosis (membranopathy) due to structural and functional impairments of human β-spectrin. This mutation allows for a better understanding of the molecular mechanism(s) of one of the membranopathies, hereditary spherocytosis.

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Section: Wes Results Analysismentioning

confidence: 88%

“…Over the last decade, significant advances have been made in diagnosis and clinical management of hereditary spherocytosis and other erythrocyte diseases [22][23][24][25]. Diagnostics of hereditary spherocytosis include several research methods that are still being improved [3,26,27].…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Mutation of β-Spectrin in Hereditary Spherocytosis Using Whole Exome Sequencing

Bogusławska

Skulski

Machnicka

et al. 2021

IJMS

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“…Within our cohort of patients with CDA II enrolled in our Registry of hereditary anemias [15,25,26], we selected 28 cases showing iron overload, defined as transferrin saturation (TSAT) > 45%. We further stratified these patients into two subgroups according to the degree of anemia: (i) mild (Hb ≥ 10.0 g/dL) and (ii) moderate/severe (Hb < 10.0 g/dL) (Table 1).…”

Section: Analysis Of Iron Balance In Patients With Cda IImentioning

confidence: 99%

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Rosato

Marra

D’Onofrio

et al. 2022

IJMS

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Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.

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“…The specificity of RBC cytoskeleton ( Svetina, 2020 ) and PIEZO1 interaction with spectrin ( Dumitru et al, 2021 ) are likely responsible for differential sensitivity of the arms of the channel compared to HEK293 cells. The PIEZO1/spectrin relation is emphasized by the recent study showing a coinheritance of PIEZO1 and spectrin mutations in a cohort of 155 patients with clinical suspicion of hereditary anemia ( Andolfo et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Hereditary Xerocytosis: Differential Behavior of PIEZO1 Mutations in the N-Terminal Extracellular Domain Between Red Blood Cells and HEK Cells

et al. 2021

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Hereditary Xerocytosis, a rare hemolytic anemia, is due to gain of function mutations in PIEZO1, a non-selective cation channel activated by mechanical stress. How these PIEZO1 mutations impair channel function and alter red blood cell (RBC) physiology, is not completely understood. Here, we report the characterization of mutations in the N-terminal part of the protein (V598M, F681S and the double mutation G782S/R808Q), a part of the channel that was subject of many investigations to decipher its role in channel gating. Our data show that the electrophysiological features of these PIEZO1 mutants expressed in HEK293T cells are different from previously characterized PIEZO1 mutations that are located in the pore or at the C-terminal extracellular domain of the protein. Although RBC with PIEZO1 mutations showed a dehydrated phenotype, the activity of V598M, F681S or R808Q in response to stretch was not significantly different from the WT channels. In contrast, the G782S mutant showed larger currents compared to the WT PIEZO1. Interestingly, basal activity of all the mutated channels was not significantly altered at the opposite of what was expected according to the decreased water and cation contents of resting RBC. In addition, the features of mutant PIEZO1 expressed in HEK293 cells do not always correlate with the observation in RBC where PIEZO1 mutations induced a cation leak associated with an increased conductance. Our work emphasizes the role of the membrane environment in PIEZO1 activity and the need to characterize RBC permeability to assess pathogenicity to PIEZO1 mutants associated with erythrocyte diseases.

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Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

Cited by 30 publications

References 27 publications

Identification of a Novel Mutation of β-Spectrin in Hereditary Spherocytosis Using Whole Exome Sequencing

Identification of a Novel Mutation of β-Spectrin in Hereditary Spherocytosis Using Whole Exome Sequencing

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Hereditary Xerocytosis: Differential Behavior of PIEZO1 Mutations in the N-Terminal Extracellular Domain Between Red Blood Cells and HEK Cells

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