IDH3B – Retinitis Pigmentosa

Retinitis pigmentosa is an inherited neurodegeneration of rod and cone photoreceptors leading to progressive vision loss. Autosomal recessive variants in IDH3B, encoding the β‐subunit of mitochondrial NAD‐specific isocitrate dehydrogenase (NAD‐IDH), have been implicated in isolated retinal disease. The retina’s high metabolic demand for NADH production via NAD‐IDH suggests a tissue‐specific vulnerability when this enzyme is deficient. This summary evaluates the evidence linking IDH3B to retinitis pigmentosa.

In a landmark study, two families (PMID:18806796) with autosomal recessive retinitis pigmentosa harbored homozygous loss‐of‐function variants in IDH3B. Affected individuals from these families showed exclusive retinal degeneration with no extraocular manifestations. Segregation analysis confirmed variant co‐segregation in both pedigrees with at least two additional affected relatives. Case‐level data included five distinct splice‐site and nonsense alleles and one missense allele across unrelated probands, consistent with a loss‐of‐function mechanism.

The variant spectrum comprised seven canonical splice‐site changes (e.g., c.531+1G>C, c.532-2A>G) and three truncating alleles, including c.571C>T (p.Arg191Ter). All variants were absent or extremely rare in population databases, supporting pathogenicity under an autosomal recessive model. No founder or recurrent alleles have been reported to date.

Functional assays on patient‐derived cells demonstrated a ~300-fold increase in the Michaelis constant (K_m) for NAD (indicating drastically reduced NAD‐IDH activity) with normal NADP‐IDH function in the same tissues (PMID:18806796). These data confirm that IDH3B loss specifically impairs mitochondrial NADH production in the retina.

A mouse model study of Idh3b loss‐of‐function did not recapitulate retinal degeneration, suggesting species‐specific metabolic compensation or differences in retinal reserve capacity. This discrepancy highlights a limitation of murine models for IDH3B‐related retinal disease and underscores the unique metabolic requirements of the human retina.

Collectively, the genetic segregation in multiple families, the absence of extraocular phenotypes, and concordant cellular functional defects support a moderate to strong association between IDH3B and autosomal recessive retinitis pigmentosa. Additional case series and natural history studies are needed to define genotype–phenotype correlations and penetrance. Key take-home: Genetic testing for biallelic IDH3B loss‐of‐function variants should be considered in unexplained autosomal recessive retinitis pigmentosa.

References

• Nature genetics • 2008 • Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. PMID:18806796

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