Locus control region HS2 point mutations are generally not responsible for elevated fetal hemoglobin expression of sickle cell patients

Journal Article · Thu Sep 01 04:00:00 EDT 1994 · American Journal of Human Genetics

OSTI ID:134621

Gilman, J G ^[1]; Brinson, E C; Milner, P M ^[2]

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1. Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY (United States)
2. Medical College of Georgia, Augusta (United States); and others

The locus control region (LCR), composed of four hypersensitive sites (HS1-4) 5{prime} of the {epsilon} globin gene, confers strong, copy-number dependent expression on globin genes in transgenic mice. Several {beta}-globin gene cluster haplotypes carry the sickle cell gene, and show variable levels of fetal hemoglobin (Hb F) expression in association with DNA sequence differences in HS2, {gamma} and {beta} globin promoters, and {gamma}IVSII: The Senegal (SEN or No. 3) haplotype generally has high (>10%) Hb F, Benin (BEN or No. 19) has intermediate Hb F (but some low and some high), and Banu (BAN or No. 20) generally has low Hb F. Huisman and colleagues have proposed that `factors produced under conditions of hematopoietic stress, together with genetic determinants on the haplotype-3 like LCR sequences, allow for high level expression of {gamma} globin genes`. We have now used slot blot to screen high Hb F (>9.5%) and low Hb F cases for two of the three HS2 point mutations described by Oener et al. Comparing eight high Hb F BEN/BEN with two low Hb F BEN/BEN, all ten had the BEN mutations considered by Oener et al. to be associated with low Hb F. Comparing three high Hb F BEN/BAN with two low Hb F BEN/BAN, all five were heterozygous at three positions; this is consistent with BEN having G and T and BAN having A at both positions. DNA sequencing of HS2 for BAN, which is generally associated with low HB F, showed that the point mutations at all three positions were those seen in SEN (generally high Hb F); only the AT repeat region showed major differences, confirming results of Huisman and colleagues. Hence, if there is any effect of HS2 of the Senegal sickle cell haplotype in causing elevated Hb F under hematopoietic stress, it must be due to specific variation in the AT repeat region, which Oener et al. have suggested may bind a silencer.

• OSTI ID: 134621
• Report Number(s): CONF-941009--
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
DNA SEQUENCING
GENE MUTATIONS
GENE REGULATION
GENES
HEMOGLOBIN
NUCLEOTIDES
PATIENTS
SICKLE CELL ANEMIA
TRANSGENIC MICE