Disease relevance of PDE6B

• Transgenic mice carrying the H258N mutation in the gene encoding the beta-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness [1].
• The positive photoreceptor-rescue effect of calcium channel blockers reported in the rd mouse was thus not generalizable to another species with retinal degeneration due to mutation in the PDE6B gene [2].
• All 22 exons including 196 bp of the 5' region of the PDEB gene have been assessed for mutations by using single-strand conformational polymorphism analysis in 14 patients from 13 unrelated families with autosomal recessive retinitis pigmentosa (ARRP) [3].
• The two mutants, rd1 and rd2, thus far isolated have been analyzed for virus particle production (using radiolabeled precursors and by electron microscopy) and for the status of intracellular viral precursors [4].

High impact information on PDE6B

• Three of these encode members of the rod photoreceptor visual transduction cascade: rhodopsin, the rod cGMP-gated cation channel alpha subunit, and the beta subunit of cGMP-phosphodiesterase (PDEB) [5].
• We investigated all 22 exons of PDEB and 5'-flanking region for point mutations in 16 HD patients of different ethnic origins using single strand conformational polymorphism analysis [6].
• We show that two apoptotic pathways, one from the mitochondrion and one from the endoplasmic reticulum, are coactivated during the degenerative process in an animal model of retinitis pigmentosa, the rd1 mouse [7].
• The finding of a mutation in the beta subunit of the cyclic GMP (cGMP) phosphodiesterase gene causing retinal degeneration in mice (the Pdeb gene) prompted a search for disease-causing mutations in the human phosphodiesterase gene (PDEB gene) in patients with retinitis pigmentosa [3].
• Gene for autosomal dominant congenital stationary night blindness maps to the same region as the gene for the beta-subunit of the rod photoreceptor cGMP phosphodiesterase (PDEB) in chromosome 4p16.3 [8].

Chemical compound and disease context of PDE6B

• Calcium channel blocker D-cis-diltiazem does not slow retinal degeneration in the PDE6B mutant rcd1 canine model of retinitis pigmentosa [2].
• To study the rescue effect of antioxidants on retinal degeneration, rd1 retinas were studied in vitro and in vivo using lutein, zeaxanthin, alpha lipoic acid and reduced l-glutathione [9].

Biological context of PDE6B

• The exon organization of the PDE11A catalytic domain was very similar to those of PDE5A and PDE6B [10].
• The molecular cloning of the cDNA encoding for the PDEB represents the first step in establishing whether this gene plays a causative role in any one of the several human hereditary retinopathies or, based on its localization to chromosome 4p 16.3, in the pathogenesis of Huntington disease [11].
• This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5' untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease [12].
• Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B) [12].
• Missense mutations of the PDEB gene causing arRP have been reported in a limited region (codon 527-codon 699) in which codon 535 is located [13].

Anatomical context of PDE6B

• PURPOSE: D-cis-diltiazem, a calcium channel blocker, has been reported to enhance photoreceptor survival in the rd mouse, a model of retinitis pigmentosa (RP) resulting from mutation of the PDE6B gene [2].

Associations of PDE6B with chemical compounds

• We tested the hypothesis that diltiazem treatment would similarly rescue the canine rcd1 model of RP, which is also caused by a null mutation in the PDE6B gene [2].
• CONCLUSIONS: Isoleucine at codon 535 in the PDEB gene is conserved among various mammals [13].
• Antigen PDEB was purified from pigeon dropping extracts and characterized as a basic glycoprotein, containing 93% protein and 7% carbohydrate, with a molecular weight of approximately 51,000 [14].
• The two affected sisters are homozygous for a T to G transversion in codon 699 of the PDEB gene, leading to the substitution of a leucine by an arginine residue [15].

Other interactions of PDE6B

• Thus, this family has adCSNB caused by a different gene from the previously identified RHO, PDE6B, and GNAT1 [16].
• Individuals with CSNB in the Rambusch pedigree were found to carry the H258N allele of PDE6B (MIM# 180072); a similar mutation was not found in RP patients [1].
• These genes include rhodopsin, beta-subunit of rod cGMP phosphodiesterase (PDEB), alpha-subunit of rod cGMP phosphodiesterase (PDEA), and alpha-subunit of rod cGMP-gated channel [13].

Analytical, diagnostic and therapeutic context of PDE6B

• Immunocytochemistry in human retina showed that CRX protein was not detected until >4 weeks later at 15 weeks p.c., implying that it would be unable to transactivate PDEB, IRBP and arrestin, which were all expressed before 15 weeks [17].
• Avidin-labeled rod photoreceptors were more abundant than the TUNEL positive photoreceptors of the rd1 mouse, indicating that oxidative DNA damage precedes fragmentation [9].
• Based on their migration in immunoelectrophoresis, the antigens have been designated PDEB, 1, 2, 3 or 4 [18].

References