RDH5 – Fundus Albipunctatus

Fundus albipunctatus is a rare, autosomal recessive form of congenital stationary night blindness characterized by delayed dark adaptation and widespread white‐yellow flecks in the midperipheral retina. The disorder is caused by biallelic loss‐of‐function variants in RDH5, which encodes the 11-cis retinol dehydrogenase enzyme responsible for the conversion of 11-cis retinol to 11-cis retinal in the retinal pigment epithelium.

1. Clinical Validity

Extensive genetic and functional data establish a definitive gene–disease relationship between RDH5 and fundus albipunctatus. Over 100 unrelated probands with biallelic RDH5 variants have been reported across multiple populations, including 25 patients from 22 Japanese pedigrees (PMID:32232344), 20 Israeli patients (PMID:22815624), and founder analyses in six Japanese patients (PMID:10845614). Segregation consistent with autosomal recessive inheritance has been documented in at least 19 additional affected relatives (PMID:10369264). Functional concordance is provided by biochemical assays demonstrating loss of enzyme activity in vitro and dominant‐negative effects of certain mutants (PMID:11675386).

ClinGen category: Definitive

2. Genetic Evidence

Inheritance is autosomal recessive, with pathogenic alleles identified in homozygous or compound heterozygous states. The variant spectrum includes missense (e.g., c.839G>A (p.Arg280His)), nonsense, frameshift, splice‐site, and in‐frame indels. A recurrent founder mutation, 1085delC/insGAAG, accounts for multiple Japanese cases (PMID:10845614). Additional variants reported include c.218C>T (p.Ser73Phe) and c.712G>T (p.Gly238Trp) in unrelated families (PMID:10369264; PMID:10617778).

ClinGen genetic evidence: Strong – >100 distinct variants across >50 families, robust segregation data

3. Functional Evidence

In vitro expression of 11-cis retinol dehydrogenase mutants reveals markedly reduced protein stability, mislocalization, and loss of catalytic activity. Cross‐linking and modeling confirm a dimeric structure, and co-expression studies show trans-dominant-negative effects on residual wild-type enzyme, explaining recessive inheritance (PMID:11675386). Alternative oxidizing pathways in RPE partially compensate but cannot restore normal kinetics of dark adaptation (PMID:11153648).

ClinGen functional evidence: Moderate – concordant biochemical and cell-biological assays

4. Phenotypic Spectrum

Patients uniformly present with nyctalopia (HP:0000662) and fundus albipunctatus (HP:0030642) manifested by delayed rod and cone recovery. Macular involvement and progressive cone dysfunction occur in older individuals (PMID:32232344), and rare cases develop cone dystrophy or sectoral retinitis pigmentosa.

5. Conclusion

Biallelic RDH5 variants cause a definitive, autosomal recessive fundus albipunctatus phenotype, combining clinical stationarity of night blindness with characteristic fundus flecks and delayed dark adaptation. Genetic testing of RDH5 informs diagnosis, carrier screening, and potential future therapies aimed at visual cycle modulation.

Take-home: RDH5 sequencing should be standard in congenital night‐blindness workups, as pathogenic variants reliably predict fundus albipunctatus and guide management.

References

• Nature Genetics • 1999 • Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. PMID:10369264
• Molecular Vision • 1999 • 11-cis retinol dehydrogenase mutations as a major cause of the congenital night-blindness disorder known as fundus albipunctatus. PMID:10617778
• Investigative Ophthalmology & Visual Science • 2000 • A frequent 1085delC/insGAAG mutation in the RDH5 gene in Japanese patients with fundus albipunctatus. PMID:10845614
• The Journal of Biological Chemistry • 2001 • Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus. PMID:11675386
• Investigative Ophthalmology & Visual Science • 2020 • RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort. PMID:32232344

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