AGBL5 and Retinitis Pigmentosa

Autosomal recessive retinitis pigmentosa (RP; [MONDO:0019200]) has been increasingly attributed to biallelic variants in AGBL5 (Gene Symbol). Initial multi-ethnic exome analyses identified eight unrelated probands with RP and sensorineural hearing loss carrying compound or homozygous truncating AGBL5 alleles, with co-segregation in affected relatives ([PMID:39672920]). Subsequent case series reported two additional patients—one with a homozygous missense and one with a nonsense allele—presenting classic RP features including nyctalopia, progressive night blindness and peripheral field constriction ([PMID:38078364]). Early exome sequencing in Turkish families highlighted a homozygous p.Asp295Asn variant in two affected siblings, supported by retinal expression and mouse immunolocalization data ([PMID:26720455]).

These clinical findings are reinforced by functional assessments: three unrelated families were shown to harbor homozygous or compound heterozygous protein-truncating and missense AGBL5 variants (e.g., c.1775G>A (p.Trp592Ter)) that associate with typical rod-cone degeneration ([PMID:27842159]). Homology modelling of p.Arg281Cys and p.Arg487Ter predicted protein destabilization, and immunostaining confirmed AGBL5 localization in photoreceptor cilia, implicating loss of deglutamylase activity in disease pathogenesis ([PMID:27764769]). No pathogenic variants in canonical RP or Usher genes were detected in these cohorts, underscoring AGBL5 as the primary locus.

Mechanistically, AGBL5 encodes a cytosolic tubulin deglutamylase essential for ciliogenesis in retinal photoreceptors; loss-of-function alleles lead to aberrant polyglutamylation, ciliary dysfunction and progressive photoreceptor loss. The concordance between genetic segregation, variant spectrum (missense, nonsense, frameshift and splice-site), and in vitro/structural data supports a haploinsufficiency or null mechanism.

Overall, AGBL5 meets ClinGen’s Strong clinical validity for autosomal recessive RP based on ≥14 probands across multiple families, segregation in affected relatives, and concordant functional data. Genetic evidence is Strong (biallelic variants in unrelated cases, diverse variant classes, segregation) and functional evidence is Moderate (retinal expression, modelling, immunolocalization). No convincing conflicting data have been reported.

Key Take-home: Biallelic loss-of-function or deleterious missense variants in AGBL5 reliably cause autosomal recessive retinitis pigmentosa, warranting inclusion in diagnostic gene panels and genetic counselling.

References

• Unspecified Journal • 2023 • Title Not Provided PMID:39672920
• Ophthalmic Genetics • 2024 • Mutations in AGBL5 associated with Retinitis pigmentosa. PMID:38078364
• Investigative Ophthalmology & Visual Science • 2015 • Exome Sequencing Reveals AGBL5 as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families. PMID:26720455
• Investigative Ophthalmology & Visual Science • 2016 • Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa PMID:27842159
• Physiological Genomics • 2016 • Establishing the involvement of the novel gene AGBL5 in retinitis pigmentosa by whole genome sequencing. PMID:27764769

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