Fabry Disease: Novel α-Galactosidase A 3′-Terminal Mutations Result in Multiple Transcripts Due to Aberrant 3′-End Formation Makiko Yasuda, Junaid Shabbeer,

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Fabry Disease: Novel α-Galactosidase A 3′-Terminal Mutations Result in Multiple Transcripts Due to Aberrant 3′-End Formation Makiko Yasuda, Junaid Shabbeer, Makiko Osawa, Robert J. Desnick The American Journal of Human Genetics Volume 73, Issue 1, Pages 162-173 (July 2003) DOI: 10.1086/376608 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 3′ RACE–PCR analysis, using normal and mutant lymphoblasts. A, Design of 3′ RACE–PCR. A gene-specific sense primer (P1) at the end of exon 6 and a nested primer within the oligo(dT) anchor sequence (P2) were used. The antisense primer contained three separate termination codons, all in different reading frames. B, 3′ RACE–PCR products analyzed on a 1.5% agarose gel. Lane 1, normal control; lane 2, 1277delAA; lane 3, 1284delACTT. The American Journal of Human Genetics 2003 73, 162-173DOI: (10.1086/376608) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutant transcripts detected in the 1277delAA (A) and 1284delACTT (B) mutations. The natural polyadenylation signal, AUUAAA, or mutated AUUAAG (del2) is indicated by an underline, and the alternative signal, AAUACA, is shown in italics. The original termination codon is shown in bold. Sequences upstream of the original termination site are capitalized, whereas nonconsensus and elongated sequences are in lowercase. The mutant transcripts were designated “A1–A20” (1277delAA) and “B1–B16” (1284delACTT), and their frequencies among the 50 colonies are indicated, as well as transcript type. A bullet (•) indicates that the base was identical to the one above. The American Journal of Human Genetics 2003 73, 162-173DOI: (10.1086/376608) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 The elongated del2 mutant transcripts are cleaved at different downstream sites. Uppercase sequences are the coding region of the human α-GalA gene, and the downward arrowhead (▾) indicates the natural poly(A) site. The poly(A) sites of the mutant transcripts are shown by insertion of the corresponding transcript numbers in parentheses. Consensus AAUAAA signals are shown in bold, and the DSEs are underlined. The American Journal of Human Genetics 2003 73, 162-173DOI: (10.1086/376608) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 Elongation of the 1277delAA and 1284delACTT mutant proteins. Sequences are aligned by codons, and the corresponding amino acid is shown below each codon. Termination codons are indicated by asterisks (*). The American Journal of Human Genetics 2003 73, 162-173DOI: (10.1086/376608) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 5 Northern blot analysis of nuclear (Nuc) and cytoplasmic (Cyto) fractions in normal and patient lymphoblast lines (1277delAA and 1284delACTT). α-GalA mRNA levels were normalized against β-actin, and the ratio of normalized mutant α-GalA to wild-type α-GalA was calculated for each cellular compartment. The American Journal of Human Genetics 2003 73, 162-173DOI: (10.1086/376608) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 6 Subcellular localization of mutant proteins. Representative mutant constructs were double stained with rabbit anti–human α-GalA antibodies and either rabbit anti–human LAMP-2 (as the lysosome marker) antibodies (a) or rabbit anti–human BiP (the ER marker) antibodies (b and c). Representative staining patterns of lysosomal (a), ER (b), and undetectable (c) proteins are shown. The American Journal of Human Genetics 2003 73, 162-173DOI: (10.1086/376608) Copyright © 2003 The American Society of Human Genetics Terms and Conditions