Architecture of the canine IDUA gene and mutation underlying canine mucopolysaccharidosis I.

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease caused by deficiency of alpha-L-iduronidase. In addition to the well-known human forms (Hurler, Hurler/Scheie, and Scheie syndromes), there exists a canine model of the disease. By using previously described canine cDNA encoding alpha-L-iduronidase as a probe, the canine IDUA gene has been cloned and characterized. It contains 14 exons spread over 13 kb. An unusual GC dinucleotide was found at the donor splice site of intron 11. A transcriptional start site was identified by primer extension 177 bp upstream of the initiator AUG codon. The upstream region was found to be similar to the promoter region of many housekeeping genes: it is GC rich and has seven potential Sp1 binding sites but no TATA box or CAAT motif. The mutation in canine MPS I was localized to the area of intron 1 by RT-PCR, identified by sequence analysis of amplified genomic DNA, and confirmed by restriction analysis; it is a G-->A transition in the donor splice site of intron 1. The mutation causes retention of intron 1 in the RNA and creates a premature termination codon at the exon-intron junction.