Heterogeneity in the molecular basis of three types of hereditary persistence of fetal hemoglobin and the relative synthesis of the G? and A? types of ? chain

Abstract

Restriction endonuclease analyses of DNA from one Black G gamma A gamma-HPFH homozygote and four Black and one Indian G gamma A gamma-HPFH heterozygotes have identified three different HPFH types which are the result of large deletions including the delta and beta genes. Two of the types are comparable to those characterized previously, but the third, which is present in the Indian heterozygote, shows a distinct difference in the size of the deletion. The 5' end point of the deletion in this type III G gamma A gamma-HPFH extends 0.5-1.0 kb beyond the 5' end point of one of the Black types of HPFH (type I). Each of the three types is associated with a distinct ratio between the G gamma and the A gamma chains, an observation supported by family data. The highest ratio is found in the heterozygote with the Indian type III G gamma A gamma-HPFH, with 69.3% G gamma chains, while the averages for the other types were 50.7% G gamma (type I) and 32.3% G gamma (type II).

High Levels of Human γ-Globin Gene Expression in Adult Mice Carrying a Transgene of Deletion-Type Hereditary Persistence of Fetal Hemoglobin

“…In contrast, transcripts from the LCR-proximal G ␥-globin gene were about three-to sevenfold higher than those of the more distal A ␥-globin gene in both non-HPFH control lines. This latter finding is consistent with results of studies with transgenic mice that examined the role of gene order on the level of expression of individual genes in the ␤-globin locus and found that an LCR-proximal gene is expressed at a higher level than a structurally similar gene located more distally (13,24,31 (27). Interestingly, the same study showed that HPFH-1 heterozygotes expressed almost equal amounts of G ␥-and A ␥-globin chains (27).…”

Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

“…This study provides proof of concept for developing a potential new approach to autologous transplantation therapy for the treatment of homozygous β-thalassemia and SCD. molecular level (12,13,(19)(20)(21)(22)(23)(24) (Fig. S1A).…”

Detection of non-deletional type of hereditary persistence of fetal hemoglobin (HPFH) condition associated with 619 bp β°-thalassemia deletion

“…Linkage analyses in samples from a large Indian family showed that the genetic determinant for HPFH segregates independently from the 7~J~ gobin gene complex (12,13). Deletional type of Indian HPFH has its 5'breakpoint within the Alu repeat 3 of the A7 globin gene (14,15) and its 3' breakpoint 3' downstream of the J',-globin gene (7). Therefore, to identify the type of HPFH, a 1.214 Kbp DNA from the test and the normal samples with the view that the difference in the intensity of the amplification signal will reveal the underlying deletion if any.…”

“…Fig. 1 a, schematic representation of the physical map on the normal human f~,-globin gene cluster showing Sfi I restriction sites (21) and Indian HPFH deletion (5,7,14,15). Schematic representation of the amplification of a 1.214Kbp and a 595bp DNA fragment from (~,-globin gene is given in Fig.…”

“…Non-deletional and deletional types of HPFH have been identified in Indian subjects (7,(12)(13)(14)(15). This study was carried out to identify the type of HPFH in a family with high amounts of fetal hemoglobin.…”