Inherited Mutation in Exon 2 of GATA-1 Is Associated with a Clinical and Laboratory Picture Similar to Familial Hypocellular Myelodysplastic Syndrome (MDS).

Transcription factors, including GATA-1 protein, play a key role in controlling the cellular proliferation and differentiation of hematopoietic stem cells. Inherited missense mutations in exon 4 of GATA-1 have been found in some families, leading to a variable degree of macrothrombocytopenia with or without abnormalities in the erythrocyte lineage. Acquired mutations in exon 2 of GATA-1 have been found in Down syndrome patients with transient myeloproliferative disorder (TMD) or megakaryoblastic leukemia (AMKL). These mutations prevent the synthesis of the full length GATA-1, but allow the synthesis of a smaller form of the protein (GATA-1s). Here, we report a novel inherited mutation, in exon 2 of the GATA-1 gene, which allows only the synthesis of GATA-1s in members of a family, who present anemia and neutropenia. A man, 19 years, was referred to our hospital due to anemia manifested at 4 years of age. Blood count showed: RBC: 3.0 x10⁶/μl, HGB: 2.9g/dl, HCT: 8.3%, MCV: 94.4fl, MCH: 32.7pg, Retic: 0.6%, WBC: 2.6x10³/μl, neutrophil: 1.0x10³/μl, and PLT: 250.0x10³/μl. The peripheral blood film demonstrated anisocytosis, macrocytosis, poikilocytosis, and neutrophils with pseudo Pelger-Hüet anomaly. The bone marrow aspirate and biopsy showed moderate hypocellularity with trilineage dysplasia. The presumptive diagnosis of hypocellular MDS was established. Karyoptype: 46, XY. DEB: negative. CFU-GM: 54 colonies/ml (normal range: 0.5 x10⁴ to 1.0x10⁴). Platelet aggregation test: 0.82 mg/ml (normal range: 0.7 to 1.2), platelet aggregation to 3μM adrenaline: absent (normal: present), and platelet aggregation to 3μM ADP: second wave absent (normal: present). The number of platelets expressing GPIX glycoprotein as well as those expressing GPIb, GPIIb, and GPIIIa were similar in patient and controls. No significant differences in the mean fluorescence indexes (MFI) for GPIX (1,214.0 vs 1,015.5), GPIb (154.0 vs 136.5), and GPIIb (100.0 vs 96.1) platelet contents were found in patient and controls. In contrast, the MFI for measurement of GPIIIa was slightly lower in patient than in controls (1,538.6 vs 1,928.1). Hypocellular MDS and similar laboratory findings were also identified in 6 additional males of the same family. Hemizygous and heterozygous 332G/C mutations in exon 2 of GATA-1 were found by sequencing PCR products in 7 males and in 4 phenotypically normal females of the family, comprising three generations. Only GATA-1s, probably resulting from alternative splicing of exon 2 was identified by RT- PCR and sequencing in affected males. In heterozygous females and normal members, both isoforms of the protein were found. These results indicate that the inherited 332G/C mutation in GATA-1 is associated with a clinical and hematological picture similar to that of MDS syndrome in contrast with the other mutations in exon 2 observed in Down syndrome, which are associated with AMKL or TMD.