Mutations in the &lt;i&gt;RACGAP1&lt;/i&gt; gene cause autosomal recessive congenital dyserythropoietic anemia type III

Hernández, Gonzalo; Romero‐Cortadellas, Lídia; Ferrer‐Cortès, Xènia; Venturi, Veronica; Dessy-Rodriguez, Mercedes; Olivella, Mireia; Husami, Ammar; Soto, C. Pérez de; Morales‐Camacho, Rosario M.; Villegas, Ana; González-Fernández, Fernando-Ataúlfo; Morado, Marta; Kalfa, Theodosia A.; Quintana-Bustamante, Óscar; Pérez-Montero, Santiago; Tornador, Cristian; Segovia, José C.; Sánchez, Mayka

doi:10.3324/haematol.2022.281277

Cited by 4 publications

(6 citation statements)

References 14 publications

(21 reference statements)

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“…They present with moderate-to-severe macrocytic anemia, hepatosplenomegaly, and iron overload with no reported data on serum thymidine kinase in the described cases. 23,26…”

Section: Cda IIImentioning

confidence: 99%

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

Russo,

Iolascon,

Andolfo

et al. 2024

Int J Lab Hematology

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Hereditary dyserythropoietic anemias, or congenital dyserythropoietic anemias (CDAs), are rare disorders disrupting normal erythroid lineage development, resulting in ineffective erythropoiesis and monolinear cytopenia. CDAs include three main types (I, II, III), transcription‐factor‐related forms, and syndromic forms. The widespread use of next‐generation sequencing in the last decade has unveiled novel causative genes and unexpected genotype–phenotype correlations. The discovery of the genetic defects underlying the CDAs not only facilitates accurate diagnosis but also enhances understanding of CDA pathophysiology. Notable advancements include identifying a hepatic‐specific role of the SEC23B loss‐of‐function in iron metabolism dysregulation in CDA II, deepening CDIN1 dysfunction during erythroid differentiation, and uncovering a recessive CDA III form associated with RACGAP1 variants. Current treatments primarily rely on supportive measures tailored to disease severity and clinical features. Comparative studies with pyruvate kinase deficiency have illuminated new therapeutic avenues by elucidating iron dyshomeostasis and dyserythropoiesis mechanisms. We herein discuss recent progress in diagnostic methodologies, novel gene discoveries, and enhanced comprehension of CDA pathogenesis and molecular genetics.

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“…They present with moderate-to-severe macrocytic anemia, hepatosplenomegaly, and iron overload with no reported data on serum thymidine kinase in the described cases. 23,26…”

Section: Cda IIImentioning

confidence: 99%

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

Russo,

Iolascon,

Andolfo

et al. 2024

Int J Lab Hematology

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“…Congenital dyserythropoietic anemias (CDAs) are a group of rare hereditary disorders characterized by ineffective erythropoiesis, different morphologic changes in erythroblasts, hemolytic anemia, and hemochromatosis. The CDAs include CDA type I to type IV and X-linked thrombocytopenia with dyserythropoietic anemia (XLTDA), all caused by mutations in different genes [ 1 , 2 ]. Among them, the CDA type II (CDA II, OMIM 224100) is the most common, inherited in an autosomal recessive fashion.…”

Section: Introductionmentioning

confidence: 99%

New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II

Musri¹,

Venturi

Ferrer‐Cortès

et al. 2023

IJMS

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Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.

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“…11,12 A case of CDA type III with RACGAP1 mutation has been reported to receive PBSCT with the RIC regimen because he was transfusion dependent. 4,6 Further studies are required to reveal the role of allo-HSCT and the optimal intensity of conditioning regimen in CDA type III.…”

mentioning

confidence: 99%

“…2 Recently, mutations in RACGAP1 have been described in CDA type III families. 3,4 Most CDA type III cases present with mildto-moderate anemia, and transfusion is rarely needed. [3][4][5][6] Because of…”

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confidence: 99%

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Novel mutation in KIF23 causing congenital dyserythropoietic anemia type III in patients who underwent allogeneic hematopoietic stem cell transplantation

Fujikawa,

Uemura,

Hasegawa

et al. 2024

Pediatric Blood & Cancer

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Congenital dyserythropoietic anemia (CDA) is a rare and heterogeneous group of inherited anemias characterized by ineffective erythropoiesis and morphological abnormalities of erythrocytes. 1 CDA type III (OMIM 105600) is the rarest subtype of CDA. 1 A study in two independent families identified a causative dominant missense mutation in KIF23. 2 KIF23 encodes mitotic kinesin-like protein (MKLP1), which combines with a homodimer of the RACGAP1 protein to form centralspindlin, a key regulator of cytokinesis 2,3 Depletion of MKLP1 leads to the formation of large multinucleate erythroblasts due to cytokinesis failure. 2 Recently, mutations in RACGAP1 have been described in CDA type III families. 3,4 Most CDA type III cases present with mildto-moderate anemia, and transfusion is rarely needed. [3][4][5][6] Because of

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Mutations in the <i>RACGAP1</i> gene cause autosomal recessive congenital dyserythropoietic anemia type III

Abstract: Not available.

Cited by 4 publications

References 14 publications

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II

Novel mutation in KIF23 causing congenital dyserythropoietic anemia type III in patients who underwent allogeneic hematopoietic stem cell transplantation

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