X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

Sankaran, Vijay G.; Ulirsch, Jacob C.; Tchaikovskii, Vassili; Ludwig, Leif S.; Wakabayashi, Aoi; Kadirvel, Senkottuvelan; Lindsley, R. Coleman; Bejar, Rafael; Shi, Jiahai; Lovitch, Scott B.; Bishop, David F.; Steensma, David P.

doi:10.1172/jci78619

Cited by 42 publications

(50 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In hematology, WES has been extremely useful for identifying unknown genetic etiologies for various disorders, such as those affecting red blood cell (RBC) production, including Diamond-Blackfan anemia and congenital dyserythropoietic anemia (3)(4)(5), disorders of RBC structure and function (6,7), and disorders affecting other aspects of hematologic function (2,8). Despite this considerable success, however, more than 50% of cases of presumed monogenic diseases are refractory to current WES approaches (9).…”

Section: Mendelian Erythroid Disordersmentioning

confidence: 99%

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

Wakabayashi

Ulirsch

Ludwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.GATA1 | cis-regulatory elements | noncoding mutations | Mendelian erythroid disorders W hole-exome sequencing (WES) and targeted sequencing approaches have greatly accelerated our ability to identify causal genetic lesions in both previously implicated and novel genes underlying monogenic disorders (1, 2). In hematology, WES has been extremely useful for identifying unknown genetic etiologies for various disorders, such as those affecting red blood cell (RBC) production, including Diamond-Blackfan anemia and congenital dyserythropoietic anemia (3-5), disorders of RBC structure and function (6, 7), and disorders affecting other aspects of hematologic function (2, 8). Despite this considerable success, however, more than 50% of cases of presumed monogenic diseases are refractory to current WES approaches (9). Although resolving these remaining cases will benefit from improvements in exome capture (10), read alignment (11), and variant annotation methodologies (11), the importance of genetic variation occurring within regulatory elements (REs) outside of the traditionally investigated coding sequences in hematologic and other diseases is being increasingly appreciated (12).Whole-genome sequencing (WGS) approaches are becoming progressively more available and affordable, but separating pathogenic genetic variation from benign or unrelated mutations remains especially difficult outside of protein-coding gen...

show abstract

Section: Mendelian Erythroid Disordersmentioning

confidence: 99%

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

Wakabayashi

Ulirsch

Ludwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although XLSA should show an X-linked inheritance pattern, several female patients with heterozygous ALAS2 mutation have been reported [55,[65][66][67][68][69][70][71][72][73], and approximately 25% of patients with pyridoxine-refractory anemia are female [74]. Two different mechanisms are proposed for female patients with heterozygous mutations of the ALAS2 gene.…”

Section: Sideroblastic Anemia In Female Patients With Alas2 Mutationmentioning

confidence: 99%

“…Sankaran et al [72] studied a pedigree of macrocytic anemia, and found that the patients in this pedigree, who were heterozygous for a missense mutation in the ALAS2 gene, were all female. In vitro experiments using recombinant proteins showed that this mutation severely impairs the binding of cofactor to ALAS2 protein, resulting in the destabilization of the enzyme.…”

Section: Sideroblastic Anemia In Female Patients With Alas2 Mutationmentioning

confidence: 99%

Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia

Furuyama

Kaneko

2017

Int J Hematol

View full text Add to dashboard Cite

Sideroblastic anemias are anemic disorders characterized by the presence of ring sideroblasts in a patient's bone marrow. These disorders are typically divided into two types, congenital or acquired sideroblastic anemia. Recently, several genes were reported as responsible for congenital sideroblastic anemia; however, the relationship between the function of the gene products and ring sideroblasts is largely unclear. In this review article, we will focus on the iron metabolism in erythroid cells as well as in patients with congenital sideroblastic anemia.

show abstract

“…A deleterious ALAS2 mutation causing X-linked macrocytic dyserythropoietic anemia in females was reported recently. 6 Variable phenotypic expression and penetrance of XLSA…”

Section: Classification Of Sideroblastic Anemiasmentioning

confidence: 99%

Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing

Cazzola

Malcovati

2015

Hematology

View full text Add to dashboard Cite

The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow. X-linked sideroblastic anemia (XLSA) is caused by germline mutations in ALAS2. Hemizygous males have a hypochromic microcytic anemia, which is generally mild to moderate and is caused by defective heme synthesis and ineffective erythropoiesis. XLSA is a typical iron-loading anemia; although most patients are responsive to pyridoxine, treatment of iron overload is also important in the management of these patients. Autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38, a member of the mitochondrial carrier family, is a severe disease: patients present in infancy with microcytic anemia, which soon becomes transfusion dependent. Conservative therapy includes regular red cell transfusion and iron chelation, whereas allogenic stem cell transplantation represents the only curative treatment. Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized mainly by anemia attributable to ineffective erythropoiesis. The clinical course of RARS is generally indolent, but there is a tendency to worsening of anemia over time, so that most patients become transfusion dependent in the long run. More than 90% of these patients carry somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery. These mutations cause misrecognition of 3Ј splice sites in downstream genes, resulting in truncated gene products and/or decreased expression attributable to nonsense-mediated RNA decay; this explains the multifactorial pathogenesis of RARS. Variants of RARS include refractory cytopenia with multilineage dysplasia and ring sideroblasts, and RARS associated with marked thrombocytosis; these variants involve additional genetic lesions. Inhibitors of molecules of the transforming growth factor-␤ superfamily have been shown recently to target ineffective erythropoiesis and ameliorate anemia both in animal models of myelodysplastic syndrome and in RARS patients. Learning Objectives• To learn the 2 genes most commonly responsible for congenital sideroblastic anemia • To understand that X-linked sideroblastic anemia is an iron-loading anemia and that treatment of iron overload is at least as important as pyridoxine administration in the management of these patients • To understand that SLC25A38-mutant autosomal recessive sideroblastic anemia is a severe disease whose only curative treatment is allogenic hematopoietic stem cell transplantation • To describe the somatic mutations of RNA splicing machinery that are found in refractory anemia with ring sideroblasts and related myeloid neoplasms • To understand that SF3B1-mutant myelodysplastic syndrome represents a distinct entity • To describe the novel drugs that target ineffective erythropoiesis in patients with refractory anemia with ring sideroblastsThe sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severit...

show abstract

X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

Cited by 42 publications

References 22 publications

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia

Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing

Contact Info

Product

Resources

About