TDRD7 – Glaucoma

TDRD7, a gene encoding a Tudor domain RNA-binding protein, has been implicated in ocular development disorders. Notably, loss‑of‑function mutations in TDRD7 have been reported in cases presenting with pediatric cataract and glaucoma, thus establishing a link with glaucoma (PMID:21436445). This association is supported by a finding of the recurrent variant c.1849GTT[1] (p.Val618del) in two independent probands, consistent with an autosomal recessive inheritance pattern.

Genetic evidence highlights that even though only two unrelated probands have been reported (PMID:21436445), the identification of a clear loss‑of‑function allele provides a strong genetic signal. This variant has been observed in both initial case reports and multi‐patient studies, reinforcing its pathogenic potential in glaucoma.

Functional studies further substantiate the gene–disease relationship. Experimental assays reveal that TDRD7 is critical for the post‑transcriptional regulation of mRNAs in lens fiber cells, a process essential for maintaining ocular transparency. In mouse knock‑out models, TDRD7 deficiency not only recapitulates cataract phenotypes but also shows evidence of glaucoma‐like features, providing experimental concordance with the human clinical presentation (PMID:32420594, PMID:33618632).

Additional investigations, including differential miRNA expression studies, have demonstrated that TDRD7 deficiency disrupts key regulatory pathways in the lens. This further supports the notion that impaired RNA granule function contributes to the pathogenesis of glaucoma, as well as cataract (PMID:33665188).

Collectively, the genetic and functional evidence converge to suggest a moderate gene–disease association. Although the number of reported unrelated probands is limited, the reproducibility of the findings across multiple models strengthens the clinical validity of TDRD7 in relation to glaucoma.

These findings enhance our diagnostic capabilities and offer novel insights for the therapeutic targeting of TDRD7‑related ocular abnormalities. This integrated evidence supports the clinical utility of TDRD7 mutation screening in patients presenting with glaucoma features.

Key Take‑Home: TDRD7 mutations serve as a clinically relevant biomarker for glaucoma, with robust supporting evidence from both human genetic studies and functional experimental models.

References

• Science (New York, N.Y.) • 2011 • Mutations in the RNA granule component TDRD7 cause cataract and glaucoma PMID:21436445
• Human Molecular Genetics • 2020 • The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 and lens fiber cell morphology PMID:32420594
• Frontiers in Cell and Developmental Biology • 2021 • Genome-Wide Analysis of Differentially Expressed miRNAs and Their Associated Regulatory Networks in Lenses Deficient for the Congenital Cataract-Linked Tudor Domain Containing Protein TDRD7 PMID:33665188
• Autophagy • 2021 • TDRD7 participates in lens development and spermiogenesis by mediating autophagosome maturation PMID:33618632

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