RDH12 – Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe early-onset inherited retinal dystrophy characterized by profound visual impairment. Pathogenic variants in RDH12 underlie a subset of autosomal recessive LCA cases, with biallelic variants segregating in multiple unrelated families. The association between RDH12 and Leber congenital amaurosis meets the ClinGen category of Strong evidence based on the number of probands, segregation data, and concordant experimental studies. This classification supports diagnostic decision-making, commercial genetic testing, and future therapeutic development.

RDH12-related LCA follows an autosomal recessive inheritance pattern. Initial Sanger sequencing in a Chinese family identified compound heterozygous missense variants c.164C>A (p.Thr55Lys) cosegregating with disease in two affected siblings (PMID:28471114). Larger cohort screening in 1011 individuals with autosomal recessive retinal dystrophy revealed RDH12 mutations in 22 probands, representing 2.2% of cases (PMID:16269441). Segregation analysis across more than 12 families confirms the recessive transmission and pathogenicity of diverse RDH12 alleles.

The RDH12 variant spectrum comprises predominantly missense substitutions and frameshift or nonsense loss-of-function alleles. Over 20 distinct pathogenic variants have been reported, including recurrent or founder alleles such as p.Leu99Ile and p.Ala269GlyfsTer2. Missense changes cluster in the catalytic core, while truncating variants disrupt protein stability. Population frequencies are negligible in control cohorts, underscoring their rarity and pathogenic relevance.

Functional studies demonstrate that RDH12 mutations impair the visual cycle by reducing 11-cis retinal synthesis. Eleven missense variants exhibited profound loss of catalytic activity and decreased protein stability when expressed in COS-7 cells (PMID:16269441). A recombinant AAV vector expressing human RDH12 restored retinal reductase activity and protected Rdh12-/- mouse retinas from light-induced damage, indicating potential for gene replacement therapy (PMID:31237438).

Conflicting evidence arises from targeted Rdh12 knockout mice, which displayed normal retinal histology, retinoid levels, and ERG responses, suggesting species-specific compensation in the visual cycle (PMID:17130236). This discrepancy highlights limitations of murine models and reinforces reliance on human genetic and cellular data.

In summary, autosomal recessive RDH12 variants cause Leber congenital amaurosis through loss of enzyme function in the visual cycle. The strong genetic and functional evidence supports RDH12 sequencing in clinical diagnostics and provides a rationale for gene therapy trials. Key Take-home: RDH12 testing is essential for accurate LCA diagnosis and therapeutic eligibility.

References

• Journal of Zhejiang University. Science. B • 2017 • Phenotype-genotype correlation with Sanger sequencing identified retinol dehydrogenase 12 (RDH12) compound heterozygous variants in a Chinese family with Leber congenital amaurosis. PMID:28471114
• Human molecular genetics • 2005 • Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. PMID:16269441
• Human gene therapy • 2019 • Development of a Gene Therapy Vector for RDH12-Associated Retinal Dystrophy. PMID:31237438
• Molecular and cellular biology • 2007 • Targeted disruption of the murine retinal dehydrogenase gene Rdh12 does not limit visual cycle function. PMID:17130236

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