Hb E is probably the most common structurally abnormal hemoglobin in the world, occurring at high frequency in Southeast Asia, where there are at least 1 million homozygotes and 30 million heterozygotes. Hb E is a β- globin variant (p.Glu26lys) that reduces the rate of synthesis of the abnormal β chain. It is another example of a coding sequence variant that impairs normal splicing by activating a cryptic splice site (see Fig. 1D). Although Hb E homozygotes are asymptomatic and only mildly anemic, individuals who are genetic compounds of Hb E and another β- thalassemia allele have clinically relevant phenotypes that are largely determined by the severity of the other allele.

Fig4. Examples of variants that disrupt normal splicing of the β- globin gene to cause β- thalassemia. (A) Normal splicing pattern. (B) An intron 2 variant (IVS2- 2A>G) in the normal splice acceptor site aborts normal splicing. This variant results in the use of a cryptic acceptor site in intron 2. The cryptic site conforms perfectly to the consensus acceptor splice sequence (where Y is either pyrimidine, T or C). Because exon 3 has been enlarged at its 5′ end by inclusion of intron 2 sequences, the abnormal alternatively spliced messenger RNA (mRNA) made from this mutant gene has lost the correct open reading frame and cannot encode β- globin. (C) An intron 1 variant (G > A in nucleotide 110 of intron 1) activates a cryptic acceptor site by creating an AG dinucleotide and increasing the resemblance of the site to the consensus acceptor sequence. The globin mRNA thus formed is elongated (19 extra nucleotides) at the 5′ side of exon 2; a premature stop codon is introduced into the transcript. A β+ thalassemia phenotype results because the correct acceptor site is still used, although at only 10% of the wild- type level. (D) In the Hb E defect, the missense variant (p.Glu26lys) in codon 26 in exon 1 activates a cryptic donor splice site in codon 25 that competes effectively with the normal donor site. Moderate use is made of this alternative splicing pathway, but the majority of RNA is still processed from the correct site, and mild β+ thalassemia results. (Modified from Stamatoyannopoulos G, Grosveld F: Hemoglobin switching. In Stamatoyannopoulos G, Majerus PW, Perlmutter RM, et al, editors: The molecular

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Polyglutamine Disorders

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