© 1995 Oxford University Press
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Deletion of the C-terminal end of aspartylgiucosaminidase resulting in a lysosomal accumulation disease: evidence for a unique genomic rearrangement
Department of Human Molecular Genetics, National Public Health Institute Mannerheimintie 166, FIN-00300, Helsinki, Finland
*To whom correspondence should be addressed
Received October 24, 1994; Revised December 14, 1994; Accepted December 14, 1994
Aspartyiglucosaminuria (AGU) is an inborn error of glycoprotein catabolism and represents the only known human deficiency of an amidase, aspartyiglucosaminidase (AGA, EC 3.5.1.26 [EC] ). We report here a detailed characterization of a unique 2 kb deletion of the AGA gene in a North American AGU patient. To facilitate the characterization of the deletion, genomic lamda clones spanning the 3' flanking region of human AGA were isolated and sequenced. The breakpoint of the deletion was determined from the patient's DNA by sequencing the genomic region containing the novel junction. The rearrangement involved a nonhomologous recombination with only 2 bp of homology at the deletion breakpoint. The deletion's 5' breakpoint was located in the last intron of AGA, thus abolishing the normal C-terminal exon. This is in contrast to our previous findings indicating that the deletion in the AGA gene would contain only the complete 3' untranslated region and leave the coding region intact (1). The unique feature of this deletion is a triplication of 19 thymidine nucleotides of an inverted Alu repeat, which is located at the deletion 3' breakpoint. The analysis of the patient's AGA cONA revealed an open reading frame containing a novel C-terminal exon, coding for a 64 amino acid sequence, which has no homology to the normal exon 9 of AGA. This new exon has a functional splice acceptor site at its 5' end, a stop codon, and a polyadenylation signal at the 3' end. Expression of the mutant AGA cDNA in COS cells showed that mutant mRNA is synthesized in equal amounts compared with normal. However, the mutant polypeptide precursor is not processed into the mature subunits of AGA, and is totally degraded within 24 h of synthesis.
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