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Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase.

ABSTRACT: Retinal degeneration in the rd mouse is inherited as an autosomal recessive trait and is caused by a defect in the gene encoding the beta subunit of cGMP phosphodiesterase. Recently, a close genetic association of the rd gene with an endogenous xenotropic murine leukemia virus (Xmv-28) was established by linkage analysis using recombinant inbred strains of mice. In this study, genomic DNA mapping and sequence analyses clarify the position of the proviral sequences in relation to the rd gene. We find that the Xmv-28 provirus is integrated into intron I of the rd gene 1511 bp downstream of the exon-intron boundary. The transcriptional orientation of the provirus is opposite to that of the gene for the beta subunit of cGMP phosphodiesterase. Reverse transcription-PCR demonstrates that the integrated Xmv-28 sequences are transcribed in the retina. The provirus is present in every strain of rd mouse tested.

SUBMITTER: Bowes C

PROVIDER: S-EPMC46215 | biostudies-other | 1993 Apr

REPOSITORIES: biostudies-other

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Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase.

Bowes C C Li T T Frankel W N WN Danciger M M Coffin J M JM Applebury M L ML Farber D B DB

Proceedings of the National Academy of Sciences of the United States of America 19930401 7

Retinal degeneration in the rd mouse is inherited as an autosomal recessive trait and is caused by a defect in the gene encoding the beta subunit of cGMP phosphodiesterase. Recently, a close genetic association of the rd gene with an endogenous xenotropic murine leukemia virus (Xmv-28) was established by linkage analysis using recombinant inbred strains of mice. In this study, genomic DNA mapping and sequence analyses clarify the position of the proviral sequences in relation to the rd gene. We ...[more]

PMID: 8385352

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Project description:We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.

Dataset Information

Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase.

Publications

Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase.

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