title: Beta+45 G --> C: a novel silent beta-thalassaemia mutation, the first in the Kozak sequence.
abstract: A family from the Southeast of Italy was found to have a novel beta-globin mutant, beta+45 G-->C, with the features of a silent beta-thalassaemia mutation. It was asymptomatic in two heterozygotes, but its interaction with the severe thalassaemia mutation beta-IVS-II-654 C-->T worsened the haematological and biosynthetic phenotype in two compound heterozygotes; moreover, another compound heterozygote, who was also heterozygote for the alphaalphaalpha(anti3.7), suffered from thalassaemia intermedia. The mutation was found associated in cis with the IVS-II-754 T-->C substitution, which did not lead to abnormally spliced mRNA. Furthermore, the amount of beta+45 mRNA was the same as the betaA mRNA in the reticulocytes of the carriers. In vitro transcription/translation experiments demonstrated that the beta+45 G-->C decreased the efficiency of translation of the beta-globin chain by about 30%: this slight impairment was consistent with the observed clinical phenotype. The beta+45 G-->C is the first mutation found in the Kozak sequence (GACACCATGG) of the beta-globin gene and the first one at the position -6 upstream the ATG. The Kozak consensus sequence plays a major role in the initiation of translation process. The present finding supports the hypothesis that the G in position -6 is important in this process.
authors.affiliation: Istituto di Genetica e Biofisica Adriano Buzzati Traverso, CNR Via G. Marconi 10-12, 80125 Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: De Angioletti
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Lacerra
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sabato
authors.forename: Clementina
authors.initials: C
authors.lastname: Carestia
mesh_terms: D000328:Adult; D005260:Female; D005914:Globins / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D005914:Globins