RGD Reference Report - X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. - Rat Genome Database

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X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction.

Authors: Yu, C  Niakan, KK  Matsushita, M  Stamatoyannopoulos, G  Orkin, SH  Raskind, WH 
Citation: Yu C, etal., Blood. 2002 Sep 15;100(6):2040-5.
RGD ID: 10450747
Pubmed: PMID:12200364   (View Abstract at PubMed)
PMCID: PMC2808424   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2002-02-0387   (Journal Full-text)

Transcription factor GATA-1 is essential for the development of erythroid cells and megakaryocytes. Each of its 2 zinc fingers is critical for normal function. The C-terminal finger is necessary for DNA binding. The N finger mediates interaction with FOG-1, a cofactor for GATA-1, and also modulates DNA-binding affinity, notably at complex or palindromic GATA sites. Residues of the N finger-mediating interaction with FOG-1 lie on the surface of the N finger facing away from DNA. Strong sequence conservation of residues facing DNA suggests that this other surface may also have an important role. We report here that a syndrome of X-linked thrombocytopenia with thalassemia in humans is caused by a missense mutation (Arg216Gln) in the GATA-1 N finger. To investigate the functional consequences of this substitution, we used site-directed mutagenesis to alter the corresponding residue in GATA-1. Compared with wild-type GATA-1, Arg216Gln GATA-1 shows comparable affinity to single GATA sites but decreased affinity to palindromic sites. Arg216Gln GATA-1 interacts with FOG-1 similarly with wild-type GATA-1. Arg216Gln GATA-1 supports erythroid maturation of GATA-1 erythroid cells, albeit at reduced efficiency compared with wild-type GATA-1. Together, these findings suggest that residues of the N finger of GATA-1-facing DNA contribute to GATA-1 function apart from interaction with the cofactor FOG-1. This is also the first example of beta-thalassemia in humans caused by a mutation in an erythroid transcription factor.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Thrombocytopenia 1  IAGP 10450747associated with Beta-Thalassemia and DNA:missense mutation: :p.R216Q (human)RGD 
Thrombocytopenia 1  ISOGATA1 (Homo sapiens)10450747; 10450747associated with Beta-Thalassemia and DNA:missense mutation: :p.R216Q (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gata1  (GATA binding protein 1)

Genes (Mus musculus)
Gata1  (GATA binding protein 1)

Genes (Homo sapiens)
GATA1  (GATA binding protein 1)


Additional Information