Cerebro-oculo-facio-skeletal syndrome.

Cerebro-oculo-facio-skeletal (COFS) syndrome is an autosomal recessive inherited disorder characterized by congenital microcephaly, congenital cataracts and/or microphthalmia, arthrogryposis, severe developmental delay, severe postnatal growth failure and facial dysmorphism with prominent nasal root and/or overhanging upper lip. This syndrome is now recognized as a disorder belonging to the spectrum of inherited defects in Nucleotide Excision Repair (NER) resulting in profound photosensitivity. In COFS syndrome, as in Cockayne syndrome, DNA repair is impaired in the transcription-coupled NER pathway, but not in the global genome NER pathway. Fourteen cases so far described as COFS syndrome have been studied at the molecular levels. All mutations have been found in Cockayne syndrome gene, CSB, xeroderma pigmentosum genes, XPD and XPG and ERCC1 gene involved in the transcription-coupled NER pathway.

Adverse effects of excessive nitric oxide on cytochrome c oxidase in lenses of hereditary cataract UPL rats.

The UPL rat is a newly developed hereditary cataract model. We previously found that the ATP content in UPL rat lenses decreases during cataract development, and the decrease in ATP content causes Ca(2+)-ATPase dysfunction resulting in an elevation in Ca(2+) and cataract development. In addition, we reported that the oral administration of disulfiram and aminoguanidine ameliorates the decrease in ATP content and the elevation in Ca(2+) content in UPL rat lenses. In this study, we demonstrate the effect of nitric oxide (NO) on the expression and activity of cytochrome c oxidase (CCO) in normal and UPL rat lenses during cataract development. We also determined the effects of the oral administration of disulfiram and aminoguanidine on the mRNA expression and activity of CCO and NO production in UPL rat lenses. The expression of CCO-1 mRNA in UPL rat lenses, determined by a quantitative real-time RT-PCR method, decreased during cataract development. CCO activity in UPL rat lenses also decreased with aging. On the other hand, the oral administration of disulfiram and aminoguanidine attenuated the decrease in CCO-1 mRNA expression and CCO activity. These results suggest that excessive NO causes the decrease in CCO-1 mRNA expression and CCO activity, and that the decrease in CCO may cause the decrease in ATP production in UPL rat lenses. Disulfiram and aminoguanidine may attenuate the decrease in ATP production, resulting in a delay in cataract development.

Expression of plasma membrane Ca(2+)-ATPase in lenses from normal and hereditary cataract UPL rats.

PURPOSE: The regulation of calcium concentration in lens cells is important in the mechanisms of cataractogenesis. The Ca( 2+) level in cells is controlled by plasma membrane Ca(2+)-ATPase (PMCA). PMCA has several isoforms that are distributed in various cell types in the body. In this study, we investigated the PMCA mRNA expression in normal lenses and in lenses from rats with newly developed hereditary cataracts. METHODS: The rats used were the UPL strain of Sprague-Dawley rats, with (UPL) and without (normal) the dominant gene for cataracts. PMCA mRNA expression in the lens, brain, liver and kidney in the normal and UPL rats was detected by reverse transcription-PCR using isoform specific primers. Partial cDNA sequences of the lens PMCA were also determined. RESULTS: PMCA1, 2, 3 and 4 were expressed in the brain and kidney. Distinct from the brain, liver and kidney, only one isoform of PMCA, PMCA1b, was expressed in both normal and UPL rat lenses. Sequences of PMCA in normal and UPL rat lenses were not different. CONCLUSIONS: The present study demonstrated that PMCA1b is the only form of PMCA present in both normal and UPL rat lenses.

A frequent 1085delC/insGAAG mutation in the RDH5 gene in Japanese patients with fundus albipunctatus.

PURPOSE: To identify the frequency of a mutation of the RDH5 gene in Japanese patients with hereditary retinal degeneration and to characterize clinical findings for the patients associated with a 1085delC/insGAAG mutation in the RDH5 gene. METHODS: Mutation screening by single-strand conformation polymorphism was performed on 6 patients with fundus albipunctatus and 150 patients with autosomal recessive retinitis pigmentosa. The DNA fragment that showed abnormal mobility on SSCP was then sequenced. Clinical features were characterized by visual acuity, slit-lamp biomicroscopy, electroretinography, fluorescein angiography, kinetic visual field testing, and dark adaptometry. RESULTS: A novel 1085delC/insGAAG mutation in the RDH5 gene was identified in all 6 patients, from 4 unrelated families with fundus albipunctatus. The ophthalmic findings of each affected member were very similar, which may provide the natural course of the phenotype produced by the 1085delC/insGAAG mutation. CONCLUSIONS: A homozygous1085delC/insGAAG mutation in the RDH5 gene produces fundus albipunctatus in Japanese patients. These findings suggest that this mutation was a founder effect in Japanese patients with fundus albipunctatus.

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.