Molecular pathology of ALAS2 deficiency

Over twenty different point mutations have been described (Figure 12.3). They all map to exons 5-11, which are highly

1 kb

Fig. 12.2 The erythroid ALAS2 gene and its pathogenic mutations

ALAS2 spans about 22 kb and consists of 11 exons. Two mature forms of mRNA exist: one full-length and one shorter as a result of alternative splicing of exon 4. The functional significance of these splicing variants is not known. Exon 1 and part of exon 2 (shown in gray) form the 5'-UTR and contain the iron-responsive element (see text). The full-length mRNA (1.95 kb) encodes a protein of 522 amino acids (64.4 kDa). The mature protein derives from the cleavage of the first 49 amino-terminal amino acids (mitochondrial signal sequence) upon entry in the mitochondrion.

conserved across species. Parts of these exons are thought to contribute to the formation of the catalytic site, the pyridoxal 5'-phosphate-binding site and the substrate-binding site of ALAS2. The presence of only missense mutations implies that hemizygotes with ALAS2 null mutations would not be viable. Very recently a nucleotide replacement at position -206 from the transcription start of ALAS2 has been found to cause SA; this is a rare example of a human disease resulting from a 'promoter-down' mutation in a gene encoding an enzyme.

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