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Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice
Journal article   Open access   Peer reviewed

Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice

Elena V. Semina, Jeffrey C Murray, Rebecca Reiter, Ronald F Hrstka and Jochen Graw
Human molecular genetics, Vol.9(11), pp.1575-1585
07/01/2000
DOI: 10.1093/hmg/9.11.1575
PMID: 10861284
url
https://doi.org/10.1093/hmg/9.11.1575View
Published (Version of record) Open Access

Abstract

Mouse aphakia (ak) is a recessive phenotype that spontaneously occurs in the 129/Sv-SlJ strain and is characterized by small eyes that lack a lens. We have recently identified a homeobox-containing gene, Pitx3, and have shown that it is expressed in the developing lens and maps to chromosome 19 close to ak in mouse. Human PITX3 gene was found to underlie anterior segment dysgenesis and cataracts. We have now obtained the entire sequence of the mouse Pitx3 gene including 10 kb of the 5' region and 5 kb of the 3' region. Of several microsatellite repeat regions identified within the Pitx3 sequence, one was informative for linkage analysis. No recombination was observed between ak and the Pitx3 marker, indicating that these two loci are closely linked (0.2 +/- 0.2 cM). Additionally, Pitx3 transcripts were not detected in the ak/ak mice either in the lens placode or at later developmental stages of the lens by in situ hybridization. Since no differences were previously found between ak/ak and wild-type sequences in the Pitx3 coding region, we hypothesized that an etiologic mutation is located in the promoter or other regulatory regions. To test this hypothesis we studied the 5' flanking region of the Pitx3 gene. This analysis revealed a deletion of 652 bp located 2.5 kb upstream from the start point of the Pitx3 5' UTR sequence in ak/ak mice. The deletion co-segregated with the ak mutation and was not detected in 16 samples from 10 different mouse strains including the founder strains. Analysis of the 652 bp region identified sequences similar to consensus binding sites for transcription factors AP-2 and Maf that were shown to play a critical role in lens determination. These lines of evidence suggest that the abnormal ocular development in the aphakia mouse is due to the deletion upstream of the Pitx3 gene.
 Sequence Deletion Molecular Sequence Data Male Genes, Homeobox - genetics Promoter Regions, Genetic - genetics Embryo, Mammalian - metabolism In Situ Hybridization Gene Expression Regulation, Developmental Mice, Mutant Strains Base Sequence Female Mice, Inbred DBA Acetyltransferases Genetic Linkage Guanine Nucleotide Exchange Factors - genetics Aphakia - genetics Aphakia - pathology Membrane Proteins - genetics Paired Box Transcription Factors Mice, Inbred C57BL Transcription Factors - genetics Mice, Inbred Strains Sequence Analysis, DNA Embryo, Mammalian - abnormalities Homeodomain Proteins - genetics Nuclear Proteins DNA - genetics DNA - chemistry Animals Muridae Mice Mice, Inbred AKR

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