RAB28 – Cone-Rod Dystrophy

Cone-rod dystrophy is a rare hereditary retinal disorder characterized by progressive degeneration of cone and rod photoreceptors, leading to visual impairment and color vision defects. RAB28 encodes a small Ras-related GTPase expressed in photoreceptor cells, where it is implicated in ciliary trafficking. The association between RAB28 and autosomal recessive cone-rod dystrophy has been classified as Strong by ClinGen based on multiple independent case series. Biallelic RAB28 variants have been reported in seven unrelated individuals from five families, including two brothers from a consanguineous pedigree identified via targeted sequencing of 125 retinal dystrophy genes in a cohort of 667 patients (PMID:32084271) and five Italian probands (PMID:33396523). Segregation of homozygous variants with disease and concordant functional assays further support a definitive gene-disease link.

RAB28-related cone-rod dystrophy follows an autosomal recessive inheritance mode. Seven probands have been documented with biallelic RAB28 alterations, including missense, splice-site, nonsense, and frameshift variants. All affected individuals presented in early adulthood with decreased visual acuity, photophobia, central outer retinal thinning, and impaired color vision. The consistency of clinical phenotypes across these independent reports underscores the gene’s role in photoreceptor integrity. No dominant or X-linked patterns have been observed, reinforcing a recessive mechanism of disease.

The variant spectrum in RAB28 is heterogeneous. Reported alterations include missense changes within conserved GTP-binding motifs (e.g., c.55G>A (p.Gly19Arg)), splice-site defects (c.76-9A>G), nonsense mutations (p.Leu13Ter, p.Trp107Ter), and frameshift deletions (p.Thr26ValfsTer4). The c.55G>A (p.Gly19Arg) change, located in the G1 box, was identified in two brothers and abolishes RAB28 localization to the primary cilium in patient fibroblasts, establishing a clear genotype–phenotype correlation.

Functional studies provide moderate evidence for a loss-of-function mechanism. Immunofluorescence microscopy demonstrated marked reduction of RAB28 at the cilium without affecting ciliogenesis in cells with the p.Gly19Arg variant (PMID:32084271). Molecular dynamics simulations of the missense p.Thr26Asn variant revealed disruption of Mg2+ coordination and impaired GTP–GDP exchange, locking Rab-28 in an inactive state (PMID:33396523). These data align with impaired ciliary trafficking as the pathogenic driver.

No conflicting evidence has been reported that disputes RAB28’s role in cone-rod dystrophy. Although deep intronic mutations in other CRD genes highlight challenges in variant detection, all RAB28 variants reported to date segregate with disease and exhibit functional impact. Alternative genetic etiologies have been ruled out in these cohorts by negative sequencing of common CRD genes such as ABCA4 and PROM1.

In summary, robust genetic and functional data classify RAB28 as a clinically valid autosomal recessive cone-rod dystrophy gene. Inclusion of RAB28 in diagnostic gene panels will improve molecular diagnosis and inform genetic counseling for affected families.

References

• Investigative ophthalmology & visual science • 2020 • A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium. PMID:32084271
• International journal of molecular sciences • 2020 • Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families. PMID:33396523

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