NM_002049.3(GATA1):c.646C>T (p.Arg216Trp) AND Thrombocytopenia, platelet dysfunction, hemolysis, and imbalanced globin synthesis

Significance: Pathogenic
ClinVar: RCV000024620

Variant: NM_002049.3(GATA1):c.646C>T (p.Arg216Trp)

Type: Variant
Allele: NM_002049.3(GATA1):c.646C>T (p.Arg216Trp) 40608
Type: single nucleotide variant
Location: ChrX: 48792370 - assembly GRCh38
ChrX: 48650777 - assembly GRCh37
References: dbSNP: 387907207
OMIM: 305371.0010


Disease: Thrombocytopenia, platelet dysfunction, hemolysis, and imbalanced globin synthesis


    In a 3-year-old boy with X-linked thrombocytopenia with beta-thalassemia (314050) and anemia, Phillips et al. (2007) identified a hemizygous mutation in the GATA1 gene, resulting in an arg216-to-trp (R216W) substitution in a highly conserved residue in the N-terminal zinc finger. The patient presented with a photosensitive bullous dermatosis and was found to have hirsutism, splenomegaly, and increased uroporphyrin with decreased UROS (606938) activity (21% of normal), consistent with a clinical diagnosis of congenital erythropoietic porphyria (CEP; 263700). However, sequencing of the UROS gene was negative. Laboratory studies showed microcytic anemia with increased reticulocytes, thrombocytopenia, increased fetal hemoglobin (59.5%), and beta-thalassemia. Bone marrow biopsy was hypercellular with dyserythropoiesis, nuclear bridging, and occasional multinucleated red cells. Megakaryocytes were decreased in number. He underwent a stem cell transplant, which was successful. The patient's mother and maternal grandmother carried the mutation in heterozygous state. The mother had had multiple first-trimester spontaneous abortions, but no signs of porphyria. The grandmother had chronic anemia and thrombocytopenia. The GATA1 gene regulates expression of UROS in developing erythrocytes, which explained the decreased UROS activity and features of porphyria. The R216W mutation affects the same residue as that reported by Yu et al. (2002) (R216Q; 305371.0006) in a family with X-linked thrombocytopenia with beta-thalassemia, but a slightly different phenotype: the anemia was less severe and fetal hemoglobin levels were not as elevated. Phillips et al. (2007) postulated that the larger, more hydrophobic tryptophan in their family would affect GATA1 binding to the UROS promoter more significantly than the smaller glutamine described by Yu et al. (2002). The striking fetal hemoglobin in the patient reported by Phillips et al. (2007) also suggested a role for GATA1 in globin chain switching.
PMID:12200364, PMID:17148589