Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have compared the sequence of the 5' hypersensitive site-2 (5'-HS-2) of the locus control region (LCR) from a sickle cell anemia (SS) patient homozygous for haplotype 19 and with low levels of fetal hemoglobin (HbF), with the same sequence from an SS patient homozygous for haplotype 3 and with high levels of HbF. Several nucleotide variations were present in the 5'HS-2 of the haplotype 19 individual. One is the A----G at position -10905 that creates an Sp1 binding site GCCCC (A----G)CCCC. A second is the T----G at position -10924 in a sequence that binds both erythroid and ubiquitous factors and exhibits high homology to the long terminal repeat of the Moloney leukemia viruses and Friend murine leukemia virus. Other differences were in the two AT-rich stretches of DNA, and an A----T substitution at position -10390. Dot-blot analyses of amplified DNA from several SS patients showed that these variations are specific for beta S chromosomes with haplotype 19. We also examined the 5'HS-2 sequence from an SS patient who is homozygous for haplotype 19, but has abnormally high levels of HbF (greater than 20%). We observed a cross-over that has placed sequences similar to the 5'HS-2 of haplotype 3 in juxtaposition to the 5' flanking regions of haplotype 19. Thus, a beta S chromosome with haplotype 19 but having a 5'HS-2 (LCR) characteristic for haplotype 3 is associated with high gamma-chain expression. We postulate 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.
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PMID:Sequence variations in the 5' hypersensitive site-2 of the locus control region of beta S chromosomes are associated with different levels of fetal globin in hemoglobin S homozygotes. 137 Jun 46

We have determined the haplotypes of 669 beta S and 109 beta A chromosomes from numerous members of 297 Nigerian families of various ethnic backgrounds. Among the beta S chromosomes, haplotype 19 was detected in 93.2%, haplotype 17 in 3.4%, and haplotype 20 in 0.1%, while 2.4% represented atypical haplotypes. As many as 60.6% of the beta A chromosomes exhibited haplotype 19 mutations, 8.2% had haplotype 3, and 1.8% had haplotype 20. Two siblings with elevated Hb F and G gamma levels were heterozygous for a beta S chromosome with haplotype 19 and a second chromosome with a hybrid haplotype (termed 19 B). In this hybrid chromosome, haplotype 3-like locus control region (LCR) [hypersensitive site-2 (HS-2)] sequences are in juxtaposition to those of the 5' flanking region of the G gamma promoter of a beta S chromosome with haplotype 19. The presence of this hybrid chromosome is associated with high G gamma values in individuals with both sickle cell anemia (SS) and sickle cell trait (AS); it closely resembles another hybrid beta S chromosome, termed 19 A, observed in a previously reported Turkish SS patient who was homozygous for this chromosome and had high Hb F and high G gamma values. In both instances, it is hypothesized that the haplotype 3-like sequences of the LCR HS-2 contain genetic determinants that can combine with factors produced during hematopoietic stress, resulting in increased gamma-globin gene expression.
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PMID:Haplotypes in SS patients from Nigeria; characterization of one atypical beta S haplotype no. 19 (Benin) associated with elevated HB F and high G gamma levels. 137 74