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GAR1 – Dyskeratosis Congenita

The GAR1 gene (HGNC:14264) has been evaluated for its potential role in dyskeratosis congenita (MONDO:0015780). Although multiple studies have identified pathogenic variants in other telomerase components such as NHP2, NOP10, DKC1, and TERT in dyskeratosis congenita probands (PMID:18523010), no definitive, causative variants in GAR1 have been reported to date. This absence of direct genetic alteration limits the overall clinical validity of the association despite GAR1 being a key component of both the telomerase and snoRNP complexes.

Functional assessments provide more robust insights into GAR1’s potential involvement in telomere biology. Experimental studies have demonstrated that GAR1 is critical for the proper SUMOylation and subnuclear localization of dyskerin, with alterations impacting telomerase RNA stabilization (PMID:33526451). While these findings support a mechanistic role for GAR1 in telomere maintenance, the lack of recurrent or segregating pathogenic variants in clinical cohorts results in a limited gene‑disease association. Key take‑home: GAR1 may modulate telomere integrity via its influence on dyskerin, representing a potential therapeutic target even though current genetic evidence remains limited.

References

  • Proceedings of the National Academy of Sciences of the United States of America • 2008 • Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita PMID:18523010
  • Molecular and cellular biology • 2021 • SUMOylation- and GAR1-Dependent Regulation of Dyskerin Nuclear and Subnuclear Localization PMID:33526451

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

No pathogenic GAR1 variants have been identified in dyskeratosis congenita patients despite GAR1's role in telomere biology (PMID:18523010).

Genetic Evidence

Limited

Genetic analyses have not revealed segregating or recurrent GAR1 mutations in affected individuals, limiting the empirical genetic support for this association (PMID:18523010).

Functional Evidence

Moderate

Functional studies indicate that GAR1 is vital for dyskerin SUMOylation and subnuclear localization, which in turn affects telomerase RNA stability (PMID:33526451).