title: A beta-thalassaemia phenotype not linked to the beta-globin cluster in an Italian family.
abstract: This paper describes a family of Central Italian origin in which three patients in two generations had either thalassaemia intermedia or a late presenting form of thalassaemia major. Sequence analysis of the patients' DNA revealed that only one of the beta-globin genes was affected by a beta-thalassaemia mutation (the codon 39 nonsense mutation), the other being completely normal, apart from the complex rearrangement (-T +ATA) at position -530 5' to the CAP site of the beta-globin gene, which has uncertain clinical significance. Haematologically, all these patients were characterized by unusually low HbF levels (1.8-7.3%) for a beta-thalassaemia major or intermedia phenotype. The mother of the two patients with thalassaemia intermedia was heterozygous for beta-thalassaemia (codon 39 nonsense mutation), while the father had thalassaemia-like red cell indices, an increased alpha/non alpha chain synthesis ratio, a slight increase of HbF and a low HbA2 level, but showed entirely normal beta-globin gene sequences, apart from the complex rearrangement (-T +ATA) at position -530 5' to the CAP site. One of the thalassaemia intermedia patients married a normal woman and they had a child with thalassaemia major who inherited only the codon 39 nonsense mutation but not the complex rearrangement at position -530. The clinical phenotype of thalassaemia-intermedia or major in the patients from this family may be explained by postulating the inheritance of the double heterozygous state for beta-thalassaemia and for a mutation in a gene coding for an erythroid-specific DNA binding protein which may impair the function of the normal beta-globin gene. Heterozygosity for this postulated mutation (father of the patients with thalassaemia intermedia) may result in the production of a beta-thalassaemia carrier state with normal HbA2 level.
authors.affiliation: Istituto di Clinica e Biologia dell'Età Evolutiva, Università degli Studi di Cagliari.
authors.forename: S
authors.initials: S
authors.lastname: Murru
authors.forename: G
authors.initials: G
authors.lastname: Loudianos
authors.forename: S
authors.initials: S
authors.lastname: Porcu
authors.forename: G V
authors.initials: GV
authors.lastname: Sciarratta
authors.forename: S
authors.initials: S
authors.lastname: Agosti
authors.forename: M I
authors.initials: MI
authors.lastname: Parodi
authors.forename: A
authors.initials: A
authors.lastname: Cao
authors.forename: M
authors.initials: M
authors.lastname: Pirastu
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015139:Blotting, Southern; D002874:Chromosome Mapping; D003062:Codon; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D005914:Globins / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D013789:Thalassemia / Q000235:genetics*
chemical_list: D003062:Codon; D005914:Globins