Molecular basis of non-deletional HPFH in Thailand and identification of two novel mutations at the binding sites of CCAAT and GATA-1 transcription factors.

High Hb F determinants are genetic defects associated with increased expression of hemoglobin F in adult life, classified as deletional and non-deletional forms. We report the first description of non-deletional hereditary persistence of fetal hemoglobin (HFPH) in Thailand. Study was done on 388 subjects suspected of non-deletional HPFH with elevated Hb F expression. Mutations in the γ- and γ-globin genes were examined by DNA analysis and rapid diagnosis of HPFH mutations were developed by PCR-based methods. Twenty subjects with five different mutations were identified including three known mutations, - 202 γ (C>T) (n = 3), - 196 γ (C>T) (n = 3), and - 158 γ (C>T) (n = 12), and two novel mutations, - 117 γ (G>C) (n = 1) and - 530 γ (A>G) (n = 1). Interaction of the - 117 γ (G>C) and Hb E (HBB:c.79G>A) resulted in elevation of Hb F to the level of 13.5%. Two plain heterozygous subjects with - 530 γ (A>G) had marginally elevated Hb F with 1.9% and 3.0%, whereas the proband with homozygous - 530 γ (A>G) had elevated Hb F of 11.5%. Functional prediction indicated that the - 117 γ (G>C) and - 530 γ (A>G) mutations dramatically alter the binding of transcription factors to respective γ-globin gene promotors, especially the CCAAT and GATA-1 transcription factors. Diverse heterogeneity of non-deletional HFPH with both known and new mutations, and complex interactions of them with other forms of thalassemia are encountered in Thai population.