Nucleotide variations in the 3' (A)γ enhancer region are linked to β-gene cluster haplotypes and are unrelated to fetal hemoglobin expression

A. Ragusa, M. Lombardo, Eric E. Bouhassira, C. Beldjord, T. Lombardo, R. L. Nagel, D. Labie, R. Krishnamoorthy

Research output: Contribution to journalArticle

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Abstract

Molecular cloning and sequence analysis of a nondeletion form of Sicilian β° hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C → T at -158 5' to (G)γ, T → C at +2285, C → A at +2476, and A → G at +2676, all 3' to (A)γ. The latter three variations in the putative (A)γ enhancer are identical to those observed in the case of Seattle HPFH. However, a severe β°-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variations, albeit an inefficient HbF production. We conclude that the variations in the (A)γ enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the β-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black β°-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between (A)γ and ψβ, which is thus the linkage disequilibrium with the variations in the (A)γ enhancer. To verify such linkage we examined samples of haplotype VI from Sicily, some with PvuII (+) site (VI(s)) and others with PvuII (-); we found the PvuII (+) haplotype VI(s) linked to C, A, and G in the (A)γ enhancer. We conclude that the PvuII site separates haplotypes in two groups linked to different variations in the 3' enhancer and should be useful in understanding the phylogeny of β-globin haplotypes.

Original languageEnglish (US)
Pages (from-to)106-111
Number of pages6
JournalAmerican Journal of Human Genetics
Volume45
Issue number1
StatePublished - 1989
Externally publishedYes

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Fetal Hemoglobin
Multigene Family
Haplotypes
Nucleotides
Sicily
Algeria
Mutation
Thalassemia
Globins
Linkage Disequilibrium
Molecular Cloning
Phylogeny
Oligonucleotides
Sequence Analysis
Digestion
Chromosomes

ASJC Scopus subject areas

  • Genetics

Cite this

Nucleotide variations in the 3' (A)γ enhancer region are linked to β-gene cluster haplotypes and are unrelated to fetal hemoglobin expression. / Ragusa, A.; Lombardo, M.; Bouhassira, Eric E.; Beldjord, C.; Lombardo, T.; Nagel, R. L.; Labie, D.; Krishnamoorthy, R.

In: American Journal of Human Genetics, Vol. 45, No. 1, 1989, p. 106-111.

Research output: Contribution to journalArticle

Ragusa, A, Lombardo, M, Bouhassira, EE, Beldjord, C, Lombardo, T, Nagel, RL, Labie, D & Krishnamoorthy, R 1989, 'Nucleotide variations in the 3' (A)γ enhancer region are linked to β-gene cluster haplotypes and are unrelated to fetal hemoglobin expression', American Journal of Human Genetics, vol. 45, no. 1, pp. 106-111.
Ragusa, A. ; Lombardo, M. ; Bouhassira, Eric E. ; Beldjord, C. ; Lombardo, T. ; Nagel, R. L. ; Labie, D. ; Krishnamoorthy, R. / Nucleotide variations in the 3' (A)γ enhancer region are linked to β-gene cluster haplotypes and are unrelated to fetal hemoglobin expression. In: American Journal of Human Genetics. 1989 ; Vol. 45, No. 1. pp. 106-111.
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abstract = "Molecular cloning and sequence analysis of a nondeletion form of Sicilian β° hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C → T at -158 5' to (G)γ, T → C at +2285, C → A at +2476, and A → G at +2676, all 3' to (A)γ. The latter three variations in the putative (A)γ enhancer are identical to those observed in the case of Seattle HPFH. However, a severe β°-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variations, albeit an inefficient HbF production. We conclude that the variations in the (A)γ enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the β-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black β°-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between (A)γ and ψβ, which is thus the linkage disequilibrium with the variations in the (A)γ enhancer. To verify such linkage we examined samples of haplotype VI from Sicily, some with PvuII (+) site (VI(s)) and others with PvuII (-); we found the PvuII (+) haplotype VI(s) linked to C, A, and G in the (A)γ enhancer. We conclude that the PvuII site separates haplotypes in two groups linked to different variations in the 3' enhancer and should be useful in understanding the phylogeny of β-globin haplotypes.",
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T1 - Nucleotide variations in the 3' (A)γ enhancer region are linked to β-gene cluster haplotypes and are unrelated to fetal hemoglobin expression

AU - Ragusa, A.

AU - Lombardo, M.

AU - Bouhassira, Eric E.

AU - Beldjord, C.

AU - Lombardo, T.

AU - Nagel, R. L.

AU - Labie, D.

AU - Krishnamoorthy, R.

PY - 1989

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N2 - Molecular cloning and sequence analysis of a nondeletion form of Sicilian β° hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C → T at -158 5' to (G)γ, T → C at +2285, C → A at +2476, and A → G at +2676, all 3' to (A)γ. The latter three variations in the putative (A)γ enhancer are identical to those observed in the case of Seattle HPFH. However, a severe β°-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variations, albeit an inefficient HbF production. We conclude that the variations in the (A)γ enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the β-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black β°-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between (A)γ and ψβ, which is thus the linkage disequilibrium with the variations in the (A)γ enhancer. To verify such linkage we examined samples of haplotype VI from Sicily, some with PvuII (+) site (VI(s)) and others with PvuII (-); we found the PvuII (+) haplotype VI(s) linked to C, A, and G in the (A)γ enhancer. We conclude that the PvuII site separates haplotypes in two groups linked to different variations in the 3' enhancer and should be useful in understanding the phylogeny of β-globin haplotypes.

AB - Molecular cloning and sequence analysis of a nondeletion form of Sicilian β° hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C → T at -158 5' to (G)γ, T → C at +2285, C → A at +2476, and A → G at +2676, all 3' to (A)γ. The latter three variations in the putative (A)γ enhancer are identical to those observed in the case of Seattle HPFH. However, a severe β°-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variations, albeit an inefficient HbF production. We conclude that the variations in the (A)γ enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the β-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black β°-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between (A)γ and ψβ, which is thus the linkage disequilibrium with the variations in the (A)γ enhancer. To verify such linkage we examined samples of haplotype VI from Sicily, some with PvuII (+) site (VI(s)) and others with PvuII (-); we found the PvuII (+) haplotype VI(s) linked to C, A, and G in the (A)γ enhancer. We conclude that the PvuII site separates haplotypes in two groups linked to different variations in the 3' enhancer and should be useful in understanding the phylogeny of β-globin haplotypes.

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