title: Molecular mechanisms of a novel β-thalassaemia mutation due to the duplication of tetranucleotide 'AGCT' at the junction IVS-II/exon 3.
abstract: We report a new β-thalassaemia allele detected in a young Italian woman, suffering with mild non-haemolytic anaemia (Hb < 10 g/dL) and not showing Hb variant or Heinz bodies. The allele is characterised by duplication of tetranucleotide 'AG/CT' (+1344/+1347) including the invariant dinucleotide 'AG' of IVS-II acceptor splicing site and the first two nucleotides of codon 105. β-Globin complementary DNA (cDNA) sequencing did not reveal any mutation and qualitative analysis of the reverse transcription PCR reaction showed that only the proximal 3' splice site present in the duplicated gene is used giving race to an anomalous messenger RNA (mRNA) present in trace (1.5 %) because, most probably, rapidly degraded. In the anomalous mRNA, the insertion causes a frameshift and synthesis of an abnormal truncated β-chain (139 residues), unable to form Hb variant because of the severe conformational changes. The duplication might have arisen from secondary structures generated by quasi-palindromic sequence 5'-CCCA(C)AG/CT(CC)TGGG-3'. Restriction fragment length polymorphism analysis for the β-globin haplotype and familiar segregation analysis indicated that the mutant β-globin gene was associated with the haplotype V.
authors: Istituto di Genetica e Biofisica 'Adriano Buzzati-Traverso', CNR, Via Pietro Castellino 111, 80131, Naples, Italy.
authors: Gennaro
authors: G
authors: Musollino
authors: Gabriella
authors: G
authors: Mastrolonardo
authors: Romeo
authors: R
authors: Prezioso
authors: Leonilde
authors: L
authors: Pagano
authors: Paola
authors: P
authors: Primignani
authors: Clementina
authors: C
authors: Carestia
authors: Giuseppina
authors: G
authors: Lacerra
mesh_terms: D000328:Adult; D000483:Alleles; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D020440:Gene Duplication; D006801:Humans; D007558:Italy; D010375:Pedigree; D011487:Protein Conformation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D012720:Severity of Illness Index; D055544:beta-Globins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D012333:RNA, Messenger; D055544:beta-Globins