Cj. Zeiss et al., TIMP-1 expression is increased in X-linked progressive retinal atrophy despite its exclusion as a candidate gene, GENE, 225(1-2), 1998, pp. 67-75
X-linked progressive retinal atrophy (XLPRA) is the only known natural anim
al model for X-linked retinitis pigmentosa (XLRP), a blinding disorder in m
an. The tissue inhibitor metalloproteinase 1 gene (TIMP-1), present in clos
e proximity to one of the two XLRP loci, was tested as a candidate for XLPR
A, 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 betw
een normal and XLPRA-affected dogs. TIMP-1 was found to be expressed in all
of the canine tissues examined by reverse transcription and polymerase cha
in reaction. The canine TIMP-1 spans 3.5 kb and is interrupted by five intr
ons with sizes comparable to those observed in the human and mouse homologu
es of the gene. The proximal promoter region of canine TIMP-1 contains sequ
ence 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 exclud
ed 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 preced
e retinal degeneration by a significant time period. (C) 1998 Elsevier Scie
nce B.V. All rights reserved.