title: Moderate reduction of beta-globin gene transcript by a novel mutation in the 5' untranslated region: a study of its interaction with other genotypes in two families.
abstract: We have identified two individuals of Greek Cypriot origin with thalassemia intermedia. Molecular analysis has shown that each individual is a compound heterozygote for a previously described beta zero thalassemia allele and a novel mutation, C-->G in position +33, in the 5' untranslated region of the beta globin gene. In both families the beta +33 allele is associated with the same beta haplotype (-++- ) suggesting that it is likely to be of a single origin, beta-cDNAs from normal and mutant beta alleles were isolated from peripheral blood reticulocytes using the technique of reverse transcription-polymerase chain reaction. Because the beta +33 (C-->G) mutation creates a cutting site for the restriction enzyme NlalV, we could demonstrate by differential restriction analysis that the beta gene with +33 mutation showed 25% to 35% residual activity compared with normal. The additive effect of this moderate deficit in beta globin production with the beta zero thalassemia mutation would explain the clinical phenotypes observed in the two probands. In contrast, two siblings of one proband who were also compound heterozygotes for the same beta thalassemia mutations, as well as heterozygotes for a nondeletional alpha thalassemia variant, and two other compound heterozygotes for the beta +33 and a beta+ thalassemia allele were completely asymptomatic. Individuals heterozygous for the beta +33 C-G mutation alone are clinically and hematologically silent, with normal red blood cell indices and normal levels of hemoglobin (Hb) A2. A direct relationship between genotypic and phenotypic severity is clearly demonstrated in these cases with obvious implications for prenatal diagnosis.
authors.affiliation: MRC Molecular Haematology Unit, John Radcliffe Hospital, Oxford, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Ho
authors.forename: J
authors.initials: J
authors.lastname: Rochette
authors.forename: C A
authors.initials: CA
authors.lastname: Fisher
authors.forename: B
authors.initials: B
authors.lastname: Wonke
authors.forename: M K
authors.initials: MK
authors.lastname: Jarvis
authors.forename: A
authors.initials: A
authors.lastname: Yardumian
authors.forename: S L
authors.initials: SL
authors.lastname: Thein
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D003535:Cyprus / Q000208:ethnology; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006041:Goats; D006239:Haplotypes / Q000235:genetics; D006443:Hemoglobin A2 / Q000032:analysis; D006579:Heterozygote; D006801:Humans; D008131:London / Q000453:epidemiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011817:Rabbits; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D017086:beta-Thalassemia / Q000208:ethnology / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D005914:Globins; D006443:Hemoglobin A2; D005319:Fetal Hemoglobin