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β+45 G → C: a novel silent β‐thalassaemia mutation, the first in the Kozak sequence
Author(s) -
De Angioletti Maria,
Lacerra Giuseppina,
Sabato Vincenzo,
Carestia Clementina
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04754.x
Subject(s) - compound heterozygosity , heterozygote advantage , mutation , mutant , biology , genetics , microbiology and biotechnology , asymptomatic , gene , messenger rna , allele , medicine
Summary A family from the Southeast of Italy was found to have a novel β ‐globin mutant, β +45 G→C, with the features of a silent β ‐thalassaemia mutation. It was asymptomatic in two heterozygotes, but its interaction with the severe thalassaemia mutation β ‐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 α α α 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 β +45 mRNA was the same as the β A mRNA in the reticulocytes of the carriers. In vitro transcription/translation experiments demonstrated that the β +45 G→C decreased the efficiency of translation of the β ‐globin chain by about 30%: this slight impairment was consistent with the observed clinical phenotype. The β +45 G→C is the first mutation found in the Kozak sequence (GACACC ATG G) of the β ‐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.