Concordance of a Point Mutation 5′ to the Gγ Globin Gene With Gγβ+ Hereditary Persistence of Fetal Hemoglobin in the Black Population

• Published in: Blood Vol. 64; no. 6; pp. 1292 - 1296
• Main Authors: Collins, Francis S., Boehm, Corinne D., Waber, Pamela G., Stoeckert, Christian J., Weissman, Sherman M., Forget, Bernard G., Kazazian, Haig H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.12.1984
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V64.6.1292.1292

Hereditary persistence of fetal hemoglobin (HPFH) is a genetically heterogeneous and clinically benign condition characterized by persistent expression of fetal hemoglobin (Hb F) into adulthood. In the Gγβ+ type, no major deletions in the globin gene cluster occur; adult heterozygotes produce approximately 20% Hb F, which results from overproduction of Gγ chains, with no apparent increase in production from the adjacent Aγ gene. We have recently described a point mutation 202 base pairs 5′ to the cap site of the Gγ gene in an individual with Gγβ+ HPFH. This mutation abolishes a normal Apal restriction endonuclease site, and thus can be detected by blotting of genomic DNA. We present here further data on the Apal mutation: (1) It occurs in six of seven families with Gγβ+ HPFH. (2) In three families, detailed haplotype analysis using 11 polymorphic restriction sites in the β globin cluster has been done. The two that carry the missing ApaI site are identical but the third, which has a normal Apal pattern, differs from the other two in at least two sites, one of which is a new polymorphic Nco I site between the δ and β globin genes. This suggests the possibility of a different HPFH mutation in the third family. (3) The haplotype of the Gγβ+ HPFH chromosome carrying the ApaI mutation is different from that of 108 βA chromosomes of black individuals that have been tested. (4) The Gγ ApaI site is normal in 61 βA and 109 βs alleles from non-HPFH black individuals, including 22 who share the same haplotype for the intragenic Gγ, Aγ HindIII polymorphisms. These data add support to the possibility that the –202 mutation is actually causative of the Gγβ+ HPFH phenotype.