A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots.

PURPOSE: To report a novel homozygous RDH5 gene mutation in a 76-year-old fundus albipunctatus who developed macular atrophy with the disappearance of white dots. DESIGN: Observational case report. METHODS: Direct genomic sequencing for RDH5 mutations was done after complete ophthalmic examination. RESULTS: Fundoscopy revealed only macular atrophy with notable absence of white dots. A homozygous G490T (Val164Phe) missense RDH5 gene mutation was detected. CONCLUSIONS: This is the first reported long-term case of fundus albipunctatus demonstrating macular atrophy with fading of the typical white dots. Gene studies may be the only method for distinguishing fundus albipunctatus from other types of macular atrophy in the elderly.

A novel Gly35Ser mutation in the RDH5 gene in a Japanese family with fundus albipunctatus associated with cone dystrophy.

OBJECTIVE: To assess the clinical and genetic characteristics of a Japanese family with fundus albipunctatus with progressive cone dystrophy associated with a mutation in the RDH5 gene. DESIGN: Case report with clinical findings and results of fluorescein angiography, electroretinograms, kinetic visual field testing, dark adaptometry, and DNA analysis. SETTING: University medical center. PATIENTS: We studied the ocular findings in 6 members of a Japanese family with fundus albipunctatus with cone dystrophy and a guanine-to-adenine transversion at the first nucleotide in codon 35 of the RDH5 gene. The mutation resulted in a substitution of serine for glycine in amino acid 35 (Gly35Ser) of the RDH5 gene. RESULTS: Characteristic features included poor night vision, white dots in the retina, cone dystrophy, and a mottled appearance of the retinal pigment epithelium. Electroretinograms showed greater impairment of the rod-mediated responses than the cone-mediated responses. After 3 hours of dark adaptation, the a and b waves and scotopic b waves recovered. CONCLUSIONS: Although the mutation of the RDH5 gene has been known as a causative gene of fundus albipunctatus, the Gly35Ser mutation in the RDH5 gene may be related to the pathogenesis of progressive retinal degeneration. This phenomenon may provide evidence of gene phenotype caused by a mutation in the RDH5 gene. CLINICAL RELEVANCE: The Gly35Ser mutation causes fundus albipunctatus with cone dystrophy. This finding provides evidence that some kinds of mutations in the RDH5 gene are related, in part at least, to the pathogenesis of progressive retinal degeneration.

Null mutation in the human 11-cis retinol dehydrogenase gene associated with fundus albipunctatus.

PURPOSE: Recent studies show that mutations in the gene encoding 11-cis retinol dehydrogenase are associated with fundus albipunctatus. The authors wanted to investigate whether additional, more severe, mutations in the 11-cis retinol dehydrogenase gene might be responsible for more severe forms of hereditary retinal diseases. DESIGN: Case-control molecular genetics study. PARTICIPANTS AND CONTROLS: Two index patients, 7 relatives, and 50 control individuals. METHODS: The authors screened two index patients diagnosed with fundus albipunctatus for mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene by direct sequencing. Control individuals were screened for the presence of the mutations using allele-specific oligonucleotide hybridization. MAIN OUTCOME MEASURES: Mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene. RESULTS: In a compound heterozygote, two novel mutations were found: a 4 bp insertion in exon 2 and a missense mutation Cys267Trp in exon 5. In a second pedigree, a homozygous frameshift mutation in codon 43 (Arg42ct[1-bpdel]) was detected. In both families, the mutations segregate with the disease. The mutations were not found in 50 control individuals. CONCLUSIONS: On the basis of our observations, it is unlikely that mutations in the 11-cis retinol dehydrogenase gene are associated with other, possibly more severe, retinal pathologic conditions/dystrophies or syndromic diseases in which the retina is also affected.

A novel compound heterozygous mutation in the RDH5 gene in a patient with fundus albipunctatus.

PURPOSE: To report a novel compound heterozygous mutation in the 11-cis retinol dehydrogenase (RDH5) gene in a patient with fundus albipunctatus. METHOD: We examined the RDH5 gene genotype in members of a Japanese family. Clinical examination showed that the proband had fundus albipunctatus and his aunt had retinitis pigmentosa. The RDH5 gene was analyzed by direct genomic sequencing. RESULTS: The proband had a compound heterozygotic missense mutation of Val177Gly (GTC-->GGC) and Arg280His (CGC-->CAC) in his RDH5 gene. His mother had the Arg280His mutation and his father had the Val177Gly mutation, but his father's aunt who has typical retinitis pigmentosa had the wild type RDH5 gene. The occurrence of Val177Gly has not been reported in the RDH5 gene of fundus albipunctatus. CONCLUSION: A novel compound heterozygous missense mutation in the RDH5 gene was found in a patient with fundus albipunctatus.

Mutations in the 11-cis retinol dehydrogenase gene in Japanese patients with Fundus albipunctatus.

PURPOSE: To detect mutations in the RDH5 gene encoding 11-cis retinol dehydrogenase in patients from Japan with fundus albipunctatus. METHODS: Polymerase chain reaction and direct genomic sequencing techniques were used to detect mutations of the RDH5 coding exons (exons 2-5) in two unrelated patients with fundus albipunctatus. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Two novel RDH5 mutations were identified. One of these was a missense mutation Val264Gly in exon 5, and the other was an in-frame insertion of 3 bp in exon 5. CONCLUSIONS: The data indicate that mutations in RDH5 are the primary cause of fundus albipunctatus.

A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.

PURPOSE: To analyze the RDH5 gene in patients with fundus albipunctatus with and without cone dystrophy and to determine whether the disease is stationary or progressive and whether the cone dystrophy is a part of fundus albipunctatus or a separate disease. METHODS: Fourteen patients from 12 separate Japanese families with fundus albipunctatus were examined. Six of the patients from 6 families also had a cone dystrophy. Genomic DNA was extracted from leukocytes of the peripheral blood, and exons 2, 3, 4, and 5 of the RDH5 gene were amplified by polymerase chain reaction and were directly sequenced. A complete ophthalmic examination was performed including best-corrected visual acuity, slit-lamp examination, indirect ophthalmoscopy, fundus photography, and electroretinography. RESULTS: In all the patients, either a homozygous mutation or compound heterozygous mutations in the RDH5 gene were identified. The identified mutations were nucleotide position (nt) 103 G to A (Gly35Ser), nt 319 G to C (Gly107Arg), nt 394 G to A (Val132Met), nt 719 G insertion (frame shift), nt 839 G to A (Arg280His), nt 841 T to C (Tyr281His), and nt 928 C to GAAG (Leu310 to GluVal). All these mutations except the Arg280His were new. The nt 928 C to GAAG mutation was detected in patients with and without cone dystrophy. Cone dystrophy was most frequently seen in patients over 40 years old. CONCLUSIONS: Fundus albipunctatus either with or without cone dystrophy is caused by mutations of the RDH5 gene. Cone dystrophy is frequently observed in elderly patients with fundus albipunctatus. The conclusion was reached that the mutations of the RDH5 gene caused a progressive cone dystrophy as well as night blindness.

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.

A point mutation (W70A) in the rod PDE-gamma gene desensitizing and delaying murine rod photoreceptors.

PURPOSE: To examine the corneal electroretinogram (ERG) of transgenic mice (W70A mice) carrying a point mutation (W70A) in the gene encoding for the gamma-subunit of rod cGMP phosphodiesterase (PDEgamma). METHODS: The ERG of W70A mice was compared with that of normal mice. Cone responses were separated from rod responses by light adaptation, whereas rod sensitivity was assessed by threshold stimulation with dim light. Spectral sensitivity curves of the ERG were obtained using a constant response criterion. RESULTS: The ERG of the W70A mouse has a desensitized, delayed rod b-wave at threshold, and a prolonged rod b-wave at higher flash intensities. The a-wave is absent even at maximal stimulation. The cone ERG of the W70A mouse is indistinguishable from that of normal mice. The spectral sensitivity of the W70A mouse is maximal in the UV spectrum, in contrast to the normal mouse, which is most sensitive in the green region of the spectrum. This supports the interpretation of the results as normal cone and abnormal rod function in the W70A mouse. CONCLUSIONS: The W70A mouse represents new model of stationary nyctalopia that can be recognized by its unusual ERG features.

Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man.

Rhodopsin kinase (RK), a specialized G-protein-coupled receptor kinase expressed in retina, is involved in quenching of light-induced signal transduction in photoreceptors. The role of RK in recovery after photoactivation has been explored in vitro and in vivo experimentally but has not been specifically defined in humans. We investigated the effects on human vision of a mutation in the RK gene causing Oguchi disease, a recessively inherited retinopathy. In vitro experiments demonstrated that the mutation, a deletion of exon 5, abolishes the enzymatic activity of RK and is likely a null. Both a homozygote and heterozygote with this RK mutation had recovery phase abnormalities of rod-isolated photoresponses by electroretinography (ERG); photoactivation was normal. Kinetics of rod bleaching adaptation by psychophysics were dramatically slowed in the homozygote but normal final thresholds were attained. Light adaptation was normal at low backgrounds but became abnormal at higher backgrounds. A slight slowing of cone deactivation kinetics in the homozygote was detected by ERG. Cone bleaching adaptation and background adaptation were normal. In this human in vivo condition without a functional RK and probable lack of phosphorylation and arrestin binding to activated rhodopsin, reduction of photolyzed chromophore and regeneration processes with 11-cis-retinal probably constitute the sole pathway for recovery of rod sensitivity. The role of RK in rods would thus be to accelerate inactivation of activated rhodopsin molecules that in concert with regeneration leads to the normal rate of recovery of sensitivity. Cones may rely mainly on regeneration for the inactivation of photolyzed visual pigment, but RK also contributes to cone recovery.

Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram but not congenital stationary night blindness.

Patients with Duchenne muscular dystrophy (DMD) have recently been reported to have an abnormal scotopic electroretinogram (ERG) showing weak rod-related responses along with a negative configuration of the bright-flash response, which has been described as being similar to the one in congenital stationary night blindness (CSNB). We compared qualitatively and quantitatively the ERGs of 6 subjects with DMD, 10 subjects with the complete form of CSNB (cCSNB), 13 subjects with the incomplete form of CSNB (iCSNB) and 1 subject with complex glycerol kinase deficiency (CGKD). The rod-related activity and the bright-flash responses were abnormal and similar in all four groups. The cone-related activity, however, was within normal limits only in the DMD group; the b-wave was subnormal in CGKD, truncated in cCSNB and nearly absent in iCSNB. The electrophysiologic signature in DMD clearly distinguishes the retinal function of these patients from any other retinal condition so far described.

Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness.

The locus for autosomal dominant congenital stationary night blindness (adCSNB) has recently been assigned to distal chromosome 4p by linkage analysis in a large Danish family. Within the candidate gene encoding the beta-subunit of rod photoreceptor cGMP-specific phosphodiesterase (beta PDE), we have identified a heterozygous C to A transversion in exon 4, predicting a His258Asp change in the polypeptide. We found a perfect cosegregation (Zmax = 22.6 at theta = 0.00) of this mutation with the disease phenotype suggesting that this missense mutation is responsible for the disease in this pedigree. Homozygous nonsense mutations in the beta PDE gene have been found recently in patients with autosomal recessive retinitis pigmentosa, a common hereditary photoreceptor dystrophy.