TOPORS – Inherited Retinal Dystrophy

TOPORS (HGNC:21653) has been implicated in autosomal dominant inherited retinal dystrophy (MONDO:0019118) presenting with prominent optic disc changes. In a single non-related family, a heterozygous p.Tyr836Cys TOPORS variant segregated with early-onset rod-cone dystrophy and peripapillary vessel attenuation in a mother and her son (2 affected), confirming dominant inheritance and co-segregation of disease (PMID:28147405).

Functional analyses reveal that post-translational regulation of TOPORS’s E3 ubiquitin ligase activity may underlie photoreceptor degeneration. Mass spectrometry and mutagenesis show that phosphorylation at Ser98 modulates ubiquitination: the phospho-deficient c.292T>G (p.Ser98Ala) mutant exhibits unchanged activity, whereas phospho-mimetic p.Ser98Asp enhances ubiquitin ligase function without affecting SUMO conjugation (PMID:19053840).

Overall, genetic evidence is limited by a single small family, while functional data provide initial mechanistic insight into TOPORS regulation. Further case series and in vivo studies are needed to confirm haploinsufficiency or dominant-negative effects in IRD. Key Take-home: Heterozygous TOPORS missense mutations represent a limited but plausible cause of autosomal dominant IRD with optic disc anomalies, supporting inclusion of TOPORS in genetic testing panels.

References

• Klinische Monatsblatter fur Augenheilkunde • 2017 • Prominent Optic Disc Featured in Inherited Retinopathy. PMID:28147405
• Biochemistry • 2008 • Identification of phosphorylation sites of TOPORS and a role for serine 98 in the regulation of ubiquitin but not SUMO E3 ligase activity. PMID:19053840

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