Haplotypes and levels of fetal hemoglobin and ^Gγ to ^Aγ ratios in mediterranean patients with thalassemia minor and major

Abstract

This study concerned the gamma chain composition of Hb F and the haplotypes of 44 patients with beta-thalassemia major or intermedia and many of their relatives. Seventeen patients came from Northern (Turkish) Cyprus, 12 from the Istanbul area, and 15 from Macedonia and Bulgaria. Analysis of the A gamma T-G gamma-A gamma I ratio was made by HPLC, while haplotyping involved seven restriction sites. Specific haplotypes were present in certain populations; haplotype I [1] is the dominant type among North Cypriot thalassemia patients. Numerous types were seen in the patients from the Balkan countries. A direct relationship between the A gamma to G gamma ratios and the haplotypes, which exists among black beta-thalassemia heterozygotes [3], was also observed among these Mediterranean patients, although such analyses were considerably complicated by extensive blood transfusion therapy. Haplotypes without the Hinc II restriction site within the psi beta gene were associated with lower G gamma values than those that had this polymorphic site. The A gamma T chain was observed in a small number of beta-thalassemia homozygotes and heterozygotes. Three thalassemia chromosomes with slightly different haplotypes and one normal chromosome with a related haplotype were associated with the gamma 75 Ile----Thr substitution. A few patients with a thalassemia intermedia were heterozygotes for beta-thalassemia with either haplotypes V or VII [1] while the "nonthalassemic" chromosome had a haplotype I, which is the most common "beta-thalassemic" haplotype among the Mediterranean population(s). Detailed analyses of this chromosome have not been completed.

Genetic factors involved in human Gγ and Aγ globin gene expression

“…On normal chromosomes 11, the alleles detected in the three families studied are: one allele associated with haplotype IX-Xmn+ and leading to high Gy values, one allele also associated with haplotype IX-XmnI + but leading to intermediary Gy values, and one allele associated with haplotype I-Xmn I and leading to low Gy values. Our assumption that normal chromosomes with haplotype IX and the Xmn I site are carrying alleles which determine relatively high Gy values fits well with the conclusions based on hemoglobinopathies study (2,3,7,8,9).…”

“…The Gy values observed in these 6 SS patients fell within a narrow range, with a mean value of 44% k 5 % . All 6 patients were found homozygous for the Benin haplotype ----+ + + defined by the Hinc I1 5' E , Hind I11 Gy, Hind 111 Ay, Hinc I1 ~ ( 3 , Hinc I1 3' ~( 3 , Ava I1 (3 and Bam H I 3' polymorphic restriction sites respectively (5). This haplotype is referred to as haplotype S , in the pedigrees.…”

“…In b-thalassemia and sickle cell anemia patients, the y globin HbF composition has been shown to be dependent on the fi globin gene cluster haplotype (2)(3)(4)(5)(6)(7) and increased Gy to Ay ratios have been found frequently associated with a C +T substitution, at position -158 5' to the Gy globin gene, detectable by DNA digestion with the enzyme XmnI (8,9). These findings strongly sug-gest that the relative expression of the Gy and Ay globin genes is controlled by a genetic factor closely linked to the fi globin gene cluster.…”

Molecular characterization of β‐globin gene mutations in Malay patients with Hb E‐β‐thalassaemia and thalassaemia major

“…Haplotype determination involved the following restriction sites: Hinc I1 5' to E; Xmn I 5' to "y; Hind 111 a t Gy and Hinc I1 at tjB and 3' to it: Ava I1 at 8. and Hpa I and Bam HI 3' to / 3 (Orkin et al, 1982). Methodology has been described before (Harano et al, 1985;Aksoy et al, 1985): the presence and absence of a restriction site are indicated by [ +] or [-I, respectively. The numbers of a-globin genes and possible abnormalities in the [-globin gene arrangement were determined in digests with several restriction enzymes and hybridization with a n tl probe and a 4 probe (Felice et al, 1986;Gu et al, 1987).…”

Hb Jambol: A New Hyperunstable Hemoglobin Causing Severe Hemolytic Anemia

“…Haplotyping was done for the 4 members of the family and involved the following restriction sites: Hin cII 5′ to ε, Hin dIII at G γ and A γ, Hin cII at ψβ and 3′ to it, Ava II at β, and Bam HI 3′ to β. The methodology and probes have been listed before [23, 24]. The number of α-globin genes was determined by gene mapping with the methodology routinely in use in our laboratory [19, 25].…”