Published online 1 December 2004
Nucleic Acids Research, Vol. 32 No. 21 © Oxford University Press 2004; all rights reserved
Paradoxical homozygous expression from heterozygotes and heterozygous expression from homozygotes as a consequence of transcriptional infidelity through a polyadenine tract in the AP3B1 gene responsible for canine cyclic neutropenia
Division of Medical Genetics/Department of Medicine, University of Washington School of Medicine, Box 357720, 1705 NE Pacific Street, HSB-K236B, Seattle, WA 98195, USA
* To whom correspondence should be addressed: Tel: +1 206 616 4566; Fax: +1 206 897 1775; Email: horwitz{at}u.washington.edu
Present address: Feng-Qian Li, Department of Pharmacology, State University of New York, Stony Brook, NY 11794, USA
Received October 4, 2004; Revised and Accepted November 11, 2004
Canine cyclic neutropenia is an autosomal recessive disease in which the number of neutrophils, the primary blood phagocyte, oscillates between almost zero and normal values with two week frequency. We previously found that the causative mutation is an insertion of an extra adenine residue within a tract of nine A's in exon 21 of the 27 exon canine AP3B1 gene. In the course of identifying the mutation, however, we observed an unusual phenomenon: heterozygous carrier dogs, who have one normal allele and one mutant allele, produce a homogeneous population of normal AP3B1 transcripts (containing nine A's), but homozygous affected dogs, who have two mutant alleles, produce a heterogeneous population of AP3B1 mRNA containing mutant transcripts with ten A's and, unexpectedly, wild-type transcripts with nine A's. By RT–PCR subclone analysis and use of an in vitro reporter assay, we show that there is a high frequency of errors made during the transcription of homopolymeric adenine sequences, such that the A tract in the mRNA is frequently shortened or lengthened by an extra residue. Out of frame transcripts are degraded, accounting for this paradox through the preferential accumulation of normal message from mutant alleles.
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