Genetic interactions in thalassemia intermedia: analysis of beta-mutations, alpha-genotype, gamma-promoters, and beta-LCR hypersensitive sites 2 and 4 in Italian patients

• Published in: American journal of hematology Vol. 48; no. 2; p. 82
• Main Authors: Camaschella, C, Mazza, U, Roetto, A, Gottardi, E, Parziale, A, Travi, M, Fattore, S, Bacchiega, D, Fiorelli, G, Cappellini, M D
• Format: Journal Article
• Language: English
• Published: United States 01-02-1995
• Subjects: Adolescent; Adult; Base Sequence; Child; Child, Preschool; Gene Deletion; Genotype; Globins - genetics; Heterozygote; Humans; Infant; Italy; Middle Aged; Molecular Sequence Data; Mutation; Phenotype; Promoter Regions, Genetic; Regulatory Sequences, Nucleic Acid; Thalassemia - genetics; Italy
• ISSN: 0361-8609
• DOI: 10.1002/ajh.2830480203

In order to verify the genetic factors influencing the clinical expression of beta-thalassemia we have studied 292 Italian patients, 165 with thalassemia intermedia and 127 with thalassemia major. The beta-globin gene mutations were defined in all cases. The number of alpha-globin genes and the integrity of specific control regions of the beta-globin cluster--gamma promoters and beta-Locus Control Region (beta-LCR)--were studied in selected cases. Homozygosity for mild mutations (group I) accounts for 24% of the intermedia patients and it is not represented among major patients. Forty-four percent of intermedia patients had combinations of mild/severe (group II) mutations and 32% had homozygosity or double heterozygosity for severe mutations (group III). Seventy-six percent of patients with thalassemia major were classified in group III and 24% in group II. Deletion type-alpha3.7 thalassemia, assessed in a part of the cases, was found in 5% of thalassemia major and 19.5% of intermedia patients in groups II and III. Structural analysis of gamma promoters and beta-LCR HS2 and HS4 regions, carried out in order to look for alterations associated with Hb F increase, did not reveal new mutations. Only rare polymorphic changes were observed at the HS2 and HS4 level. The -158G gamma C T change was found with an increased incidence in intermedia patients in groups II and III. A subset of 10 beta-thalassemia heterozygotes with mild intermedia phenotype resulted from coinheritance of a triplicated alpha-locus. We have been unable to find a molecular basis for the benign clinical course in approximately 20% of patients with thalassemia intermedia. Other genetic or acquired factors must be hypothesized which ameliorate the clinical condition.