α-Thalassaemia caused by a polyadenylation signal mutation

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Abstract
Most eukaryotic messenger RNAs have the sequence AAUAAA 11–30 nucleotides from the 3′-terminal poly(A) tract1,2. Since this is the only significant sequence homology in the 3′ non-coding region it has been suggested that it may be a recognition site for enzymes involved in polyadenylation and/or termination of polymerase II transcription2–4. This idea is strengthened by observations on the effect of deletion mutations in or around the AATAAA sequence on polyadenylation of late simian virus 40 (SV40) mRNA; removal of this sequence prevents poly(A) addition3. Naturally occurring variants ofthis hexanucleotide are rare5–11 and hitherto their functional significance has not been assessed. We have now identified a human α2-globin gene which contains a single point mutation in this hexanucleotide (AATAAA → AATAAG). The paired α1 gene on the same chromosome is completely inactivated by a frame-shift mutation. This unique combination has enabled the expression of the mutant α2 gene to be studied in vivo where it has been found that the accumulated level of α2-specific mRNA in erythroid cells is reduced. Furthermore, readthrough transcripts extending beyond the normal poly(A) addition site are detected in mRNA obtained from HeLa cells transfected with cloned DNA from the mutant α2 gene, suggesting that the single nucleotide change in the AATAAA sequence is the cause of its abnormal expression.