bims-conane 2024-11-24 papers

Transfus Med Rev. 2024 Oct 18. pii: S0887-7963(24)00051-8. [Epub ahead of print]38(4): 150861

Exploring Novel Strategies to Alleviate Symptoms of β-Globinopathies: Examining the Potential Role of Embryonic ε-globin Induction.

Jun Liu, Kevin Park, Ziyang Shen, Yuhua Ye, Ernie Lee, Ruby Adelaide Herman, Xingxin Zhu, Wen Lu, James Nuhfer, Mahmoud A Bassal, Daniel G Tenen, Patricia Brunker, Xiangmin Xu, Li Chai.

β-thalassemia and sickle cell disease are among the most prevalent genetic blood disorders globally. These conditions arise from mutations in the β-globin gene, leading to defective hemoglobin production and resulting in anemia. Current treatments include γ-globin inducers (eg, Hydroxyurea), blood transfusions, iron chelation therapy, and bone marrow transplantation. Recently approved disease-modifying agents and promising gene therapies offer hope, yet their broad application is constrained by scalability challenges. Traditionally, research and development for β-globinopathies have focused on γ-globin induction. However, the ε-globin variant, which is active during early embryonic development and subsequently silenced prenatally, was once considered noninducible by postnatal pharmacological means. Recent studies indicate that, akin to γ-globin, enhancing ε-globin expression could compensate for impaired β-globin synthesis, potentially ameliorating the clinical manifestations of β-globinopathies. This review critically examines the viability of ε-globin induction as a therapeutic strategy for β-thalassemia and sickle cell diseases. It also delves into the burgeoning research on the mechanisms governing ε-globin silencing and its pharmacological reactivation. We conclude with a discussion of prospective research directions and drug development initiatives aimed at exploiting ε-globin's therapeutic promise.

Keywords: Embryonic hemoglobin; Fetal hemoglobin; Treatment options; β-globinopathies; β-thalassemia; ε-globin

DOI: https://doi.org/10.1016/j.tmrv.2024.150861

Hemoglobin. 2024 Nov 18. 1-5

α0-Thalassemia Caused by a Novel α-Globin Gene Cluster Deletion (-LB) Found in a Chinese Family.

Li-Hua Ye, Yuan-Yuan Huang, Zhi-Tai Zhu, Ai-Qiong Jiang, Xue-Lian Shen, Liang Liang, You-Qiong Li.

We report a novel large α-globin gene cluster deletion in a Chinese family from the Guangxi Zhuang Autonomous Regionfor the first time. The proband was a 20-year-old male who presented with microcytic hypochromatosis. Routine genetic analysis showed none of the common mutations in theα-globin and β-globin genes. Multiplex ligation-dependent probe amplification (MLPA) of the α-globin chain revealed there was a large deletion, which removed the entire HBA2 and HBA1 genes, HBQ gene, HBZ gene, and major regulatory element HS-40, eliminating more than 134 kb from the α-globin chain. Subsequently, pedigree analysis revealed that the proband inherited the novel deletion from his father. By consultation of literature and databases, it was confirmed as a hitherto undescribed chain deletion and named Laibin deletion (-LB) for the origin of the proband.

Keywords: Deletion; Laibin deletion (–LB); multiplex ligation-dependent probe amplification (MLPA); thalassemia

DOI: https://doi.org/10.1080/03630269.2024.2422425

J Med Case Rep. 2024 Nov 20. 18(1): 562

A novel nonsense RPS26 mutation in a patient with Diamond-Blackfan anemia: a case report.

Şule Çalışkan Kamış, Metin Çil, Begül Yağcı, Özlem Anlaş.

BACKGROUND: Diamond-Blackfan anemia is a rare congenital disorder characterized by erythroid hypoplasia and is associated with mutations in ribosomal protein genes. This case report describes a novel variant in the RPS26 gene, which, to our knowledge, has not been previously documented. Reporting this case adds to the understanding of Diamond-Blackfan anemia's genetic diversity and phenotypic manifestations.
CASE PRESENTATION: A 16-month-old Turkish girl presented with pallor and macrocytosis. There was no familial history of anemia. Hemoglobin electrophoresis showed hemoglobin F at 10.8%, hemoglobin A2 at 1.7%, and hemoglobin A at 87.5% (normal range 0-2%). Peripheral smear demonstrated macrocytosis and reticulocytopenia. Bone marrow examination revealed marked erythroid hypoplasia and dyserythropoiesis. Targeted next-generation sequencing, which included genes such as RPL11, RPL15, RPL26, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS28, RPS29, RPS7, and TSR2, identified a heterozygous c.221G>T (p.C74F) variant in the RPS26 gene. This variant is reported here for the first time.
CONCLUSIONS: The identification of the c.221G>T (p.C74F) variant in RPS26 provides new insights into the genetic underpinnings of Diamond-Blackfan anemia. This finding underscores the importance of genetic testing in diagnosing Diamond-Blackfan anemia and highlights the potential for new mutations to contribute to the clinical presentation of the disease. Further research into RPS26 mutations may enhance the understanding of Diamond-Blackfan anemia's pathogenesis and lead to improved diagnostic and therapeutic strategies.

Keywords: RPS26 ; Case reports; Diamond–Blackfan anemia; Ribosomopathy

DOI: https://doi.org/10.1186/s13256-024-04907-3

Front Genet. 2024 ;15 1422462

A particular focus on the prevalence of α-thalassemia and β-thalassemia among pregnant women in Changsha County, Hunan Province.

Yu Xia, Cailian Huang, Mudan Yang, Meng Zhang, Yang Lu.

Background: Thalassemia is a inherited monogenic blood disorder and more prevalent in southern China. In this study, Our aim was to elucidate the molecular spectrum and phenotypic features of thalassemia in pregnant women in Changsha County.
Methods: Next-generation sequencing (NGS) was conducted for 38,810 pregnant women to diagnose thalassemia in Changsha County. Further analysis of hematological parameters was conducted on subjects who had not previously undergone thalassemia screening in other hospitals.
Results: In this study, 2,208 (5.69%) pregnant women were diagnosed as carriers of thalassemia using NGS analysis. Among 1,594 cases of α-thalassemia, 23 genotypes were identified, and among 578 cases of β-thalassemia, 22 genotypes were detected. Additionally, 18 genotypes were detected among 36 cases of composite α- and β-thalassemia. Among all carriers of thalassemia, 8 rare α-mutations and 11 rare β-mutations were found in the study population. Notably, pregnant women diagnosed as carriers of thalassemia tended to have lower hemoglobin levels. Furthermore, multivariable logistic regression analysis indicates that the values of MCV and MCH have the greatest impact on genetic diagnosis.
Conclusion: Our study has provided detailed genotypes and hematological parameters of thalassemia in pregnant women in Changsha county and reveal that certain abnormal blood parameters have a remarkably impact on genetic diagnosis results. Furthermore, our data suggest that combining hemoglobin electrophoresis and NGS provides a powerful tool for prenatal diagnosis, which will increase the accuracy of clinical diagnosis of thalassemia.

Keywords: Changsha County; hematological parameters; next-generation sequencing; pregnant women; thalassemia

DOI: https://doi.org/10.3389/fgene.2024.1422462

Am J Hematol. 2024 Nov 18.

RAS signaling pathway is essential in regulating PIEZO1-mediated hepatic iron overload in dehydrated hereditary stomatocytosis.

Barbara Eleni Rosato, Vanessa D'Onofrio, Roberta Marra, Antonella Nostroso, Federica Maria Esposito, Anthony Iscaro, Vito Alessandro Lasorsa, Mario Capasso, Achille Iolascon, Roberta Russo, Immacolata Andolfo.

PIEZO1 encodes a mechanoreceptor, a cation channel activated by mechanical stimuli. Gain-of-function (GoF) variants in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS), or xerocytosis, a pleiotropic syndrome characterized by anemia and iron overload. DHS patients develop hepatic iron overload independent of the degree of anemia and transfusion regimen. PIEZO1-GoF variants suppress hepcidin expression in both hepatic cellular model and constitutive/macrophage-specific Piezo1-GoF mice model. Therefore, PIEZO1-GoF variants regulate hepcidin expression by a crosstalk between hepatocytes (HCs) and macrophages with a still unknown mechanism. Transcriptomic and proteomics analysis in the human hepatic Hep3B cells engineered for the PIEZO1-R2456H variant (PIEZO1-KI) revealed alterations in the actin cytoskeleton regulation, MAPK cascade, and RAS signaling. These changes mainly occur through a novel key regulator, RRAS, whose protein and mRNA levels are regulated by PIEZO1 activation and inhibition. This regulation was further confirmed in C57BL/6 mouse primary HCs treated with Yoda-1 and/or GsMTx-4. Indeed, PIEZO1-KI cells exhibited hyper-activated RAS-GTPase activity that is rescued by PIEZO1 inhibition, restoring expression of the hepcidin gene HAMP. A negative correlation between RAS signaling and HAMP regulation was confirmed by inhibiting RAS-GTPase and MEK1-2 activity. Conversely, rescued HAMP gene expression requires downregulation of RRAS, confirming negative feedback between RAS-MAPK and BMP/SMADs pathways in HAMP regulation. We demonstrated that PIEZO1-GoF variants influence the actin cytoskeleton organization by activating the hepatic RAS signaling system. Understanding the role of RAS signaling in regulating iron metabolism could pave the way for new therapeutic strategies in DHS and other conditions characterized by iron overload.

DOI: https://doi.org/10.1002/ajh.27523