A novel <i><scp>GATA</scp>1</i> mutation (<scp>S</scp>top414<scp>A</scp>rg) in a family with the rare <scp>X</scp>‐linked blood group <scp>L</scp>u(a‐b‐) phenotype and mild macrothrombocytic thrombocytopenia

Singleton, Belinda K.; Roxby, David; Stirling, John W.; Spring, Frances A.; Wilson, Carolyn M.; Poole, Joyce; Anstee, David J.

doi:10.1111/bjh.12184

Cited by 32 publications

(31 citation statements)

References 11 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Four individuals who were Lu a and Lu b negative were identified from 5420 unrelated blood donors by the serologic method. No mutation was found in the full coding region of the LU and GATA1 gene in these individuals, which can exclude the individual associated with LU gene or X‐linked blood group Lu(a–b–) phenotype . Two of these individuals had normal sequence and the other individuals had different polymorphism sites in the KLF1 , including c.199A/del heterozygote, c.304T>C, and c.604G>A.…”

Section: Resultssupporting

confidence: 86%

Two novel mutations in KLF1 were identified in Chinese individuals with In(Lu) phenotype

Chen

Hong

et al. 2017

Transfusion

View full text Add to dashboard Cite

Section: Resultssupporting

confidence: 86%

Two novel mutations in KLF1 were identified in Chinese individuals with In(Lu) phenotype

Chen

Hong

et al. 2017

Transfusion

View full text Add to dashboard Cite

“…Most reported variants within GATA1 occur within the N‐terminal zinc finger domain, leading to a disruption of the binding of GATA1 to FOG1. The stop‐loss variant noted in patient 54, was first identified in a 67‐year‐old male proband who suffers from easy bruising 16 . The patient's platelet counts varied between 86 to 94 × 10 9 /L at different times of testing and no other differences in hematological cell numbers were noted.…”

Section: Resultsmentioning

confidence: 95%

“…Four pathogenic or likely pathogenic variants were identified that are previously known to cause IT. These were found in patients; 54 ( GATA1 ; c.1240T>C, p.*414Arg+41), 59 ( RUNX1 ; c.386C>A, p.Ala129Glu), 70 ( GFI1B ; c.503G>T, p.Cys168Phe), and 64 ( MYH9 ; c.2152C>T, p.Arg718Trp) 3 , 15 , 16 , 17 …”

Section: Resultsmentioning

confidence: 95%

A comprehensive targeted next‐generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia

Johnson

Doak

Allsup

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

BackgroundInherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet counts and often disproportionate bleeding with over 30 genes currently implicated. Previously the UK‐GAPP study using whole exome sequencing (WES) identified a pathogenic variant in 19 of 47 (40%) patients of which 71% had variants in genes known to cause IT.AimsTo employ a targeted next‐generation sequencing platform to improve efficiency of diagnostic testing and reduce overall costs.MethodsWe have developed an IT‐specific gene panel as a pre‐screen for patients prior to WES using the Agilent SureSelectQXT transposon‐based enrichment system.ResultsThirty‐one patients were analyzed using the panel‐based sequencing, of which; 10% (3/31) were identified with a classified pathogenic variant, 16% (5/31) were identified with a likely pathogenic variant, 51% (16/31) were identified with variants of unknown significance, and 23% (7/31) were identified with either no variant or a benign variant.Discussion and ConclusionAlthough requiring further clarification of the impact of the genetic variations, the application of an IT‐specific next generation sequencing panel is an viable method of pre‐screening patients for variants in known IT‐causing genes prior to WES. With an added benefit of distinguishing IT from idiopathic thrombocytopenic purpura (ITP) and the potential to identify variants in genes known to have a predisposition to hematological malignancies, it could become a critical step in improving patient clinical management.

show abstract

“…Additional congenital alterations in GATA1 outside the NF have been described. [49][50][51] These affect the N-terminal and C-terminal BLOOD, 27 JUNE 2013 x VOLUME 121, NUMBER 26 HEMATOLOGIC DISEASE MECHANISMS 5225…”

Section: Discussionmentioning

confidence: 99%

Analysis of disease-causing GATA1 mutations in murine gene complementation systems

Campbell

Wilkinson-White

Mackay

et al. 2013

Blood

View full text Add to dashboard Cite

Missense mutations in transcription factor GATA1 underlie a spectrum of congenital red blood cell and platelet disorders. We investigated how these alterations cause distinct clinical phenotypes by combining structural, biochemical, and genomic approaches with gene complementation systems that examine GATA1 function in biologically relevant cellular contexts. Substitutions that disrupt FOG1 cofactor binding impair both gene activation and repression and are associated with pronounced clinical phenotypes. Moreover, clinical severity correlates with the degree of FOG1 disruption. Surprisingly, 2 mutations shown to impair DNA binding of GATA1 in vitro did not measurably affect in vivo target gene occupancy. Rather, one of these disrupted binding to the TAL1 complex, implicating it in diseases caused by GATA1 mutations. Diminished TAL1 complex recruitment mainly impairs transcriptional activation and is linked to relatively mild disease. Notably, different substitutions at the same amino acid can selectively inhibit TAL1 complex or FOG1 binding, producing distinct cellular and clinical phenotypes. The structure-function relationships elucidated here were not predicted by prior in vitro or computational studies. Thus, our findings uncover novel disease mechanisms underlying GATA1 mutations and highlight the power of gene complementation assays for elucidating the molecular basis of genetic diseases. (Blood. 2013;121(26):5218-5227) IntroductionErythrocyte and megakaryocyte development are under the control of transcription factor GATA1.1,2 GATA1 promotes differentiation by activating all known erythroid-and megakaryocytespecific genes and silencing genes associated with the immature, proliferative state and alternative lineages (for review, see Ferreira et al 3 ). GATA1 contains 2 highly conserved zinc finger (ZF) domains. The C-terminal ZF primarily binds to the sequence (A/T)GATA(A/G) while the N-terminal ZF (NF) stabilizes DNA interactions by contacting noncanonical GATC and palindromic ATC(A/T)GATA(A/G) motifs. [4][5][6] The NF also binds coregulators, including the multi-ZF protein FOG1.7 Like GATA1, FOG1 is required for erythroid and megakaryocyte development, and disrupting the GATA1-FOG1 interaction impairs maturation of these lineages. [8][9][10] Activation and repression of most GATA1-regulated genes requires FOG1, 11,12 as does silencing of mast cell-specific genes.13-15 FOG1 also modulates GATA1 chromatin occupancy at a subset of genomic sites. [15][16][17] Additionally, the TAL1 complex, composed of TAL1, E2A, LMO2, and Ldb1, interacts via LMO2 with the GATA1 NF.18,19 TAL1, LMO2, and Ldb1 are essential for erythrocyte and megakaryocyte differentiation.20-22 TAL1 complex recruitment occurs predominantly at GATA1-activated genes and tends to be depleted at sites where GATA1 functions as a repressor. 23,24 The distinct interaction surfaces of GATA1 that contact DNA, FOG1, and LMO2 have been defined previously. 19,25,26 Missense mutations in the GATA1 NF cause distinct forms of congenital anemia and thrombocy...

show abstract

A novel GATA1 mutation (Stop414Arg) in a family with the rare X‐linked blood group Lu(a‐b‐) phenotype and mild macrothrombocytic thrombocytopenia

Cited by 32 publications

References 11 publications

Two novel mutations in KLF1 were identified in Chinese individuals with In(Lu) phenotype

Two novel mutations in KLF1 were identified in Chinese individuals with In(Lu) phenotype

A comprehensive targeted next‐generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia

Analysis of disease-causing GATA1 mutations in murine gene complementation systems

Contact Info

Product

Resources

About