TIMP-1 expression is increased in X-linked progressive retinal atrophy despite its exclusion as a candidate gene

X-linked progressive retinal atrophy ( XLPRA) is the only known natural animal model for X-linked retinitis pigmentosa ( XLRP), a blinding disorder in man. The tissue inhibitor metalloproteinase 1 gene ( TIMP-1), present in close proximity to one of the two XLRP loci, was tested as a candidate for XLPRA, by first characterizing the cDNA and gene from a normal dog. The cloned canine TIMP-1 cDNA is predicted to encode a protein of 207 amino acids with 66–83% identity in the deduced aa sequence with homologous mammalian genes. No sequence difference in the coding sequence of TIMP-1 was observed between normal and XLPRA-affected dogs. TIMP-1 was found to be expressed in all of the canine tissues examined by reverse transcription and polymerase chain reaction. The canine TIMP-1 spans 3.5 kb and is interrupted by five introns with sizes comparable to those observed in the human and mouse homologues of the gene. The proximal promoter region of canine TIMP-1 contains sequence motifs shown to have regulatory significance in transcription of human TIMP-1. Linkage analysis between XLPRA and TIMP-1 using a newly identified intragenic polymorphism identified recombinants, which conclusively excluded the gene as a candidate for the disease. TIMP-1 is overexpressed several months before retinal degeneration is histologically evident in XLPRA dogs, implying that alterations in interphotoreceptor matrix composition precede retinal degeneration by a significant time period.