RRAGA – Autosomal Dominant Cataract

RRAGA encodes the RagA GTPase, a critical regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and has been implicated in autosomal dominant juvenile‐onset cataracts. Initial whole‐exome sequencing in a multigenerational family identified a novel c.178T>G (p.Leu60Arg) variant that co-segregated with disease across affected members ([PMID:27294265]). Follow-up screening in 22 additional families and 142 unrelated patients revealed two more cases harboring RRAGA variants—one recurrent p.Leu60Arg and one upstream c.-16G>A—confirming independent pathogenic events ([PMID:27294265]).

Inheritance is autosomal dominant, with at least three independent probands (one family plus two singleton cases) carrying heterozygous RRAGA alleles and showing juvenile‐onset cataract phenotypes ([PMID:27294265]). Segregation in the index pedigree provided strong evidence for co-inheritance of p.Leu60Arg with cataract. No other modes of inheritance or differential phenotypes have been reported to date.

The variant spectrum currently includes one missense substitution (c.178T>G (p.Leu60Arg)) and one noncoding upstream variant (c.-16G>A). The p.Leu60Arg change affects the GTPase domain, whereas c.-16G>A likely perturbs promoter activity. Both alleles are absent from large control databases, supporting rarity and pathogenicity ([PMID:27294265]).

Functional assays in human lens epithelial cells demonstrated that RRAGA variants mislocalize to lysosomes, hyperactivate mTORC1 phosphorylation, down-regulate autophagy, alter cell growth patterns, and reduce RRAGA promoter activity, recapitulating key features of lens opacification and confirming a gain‐of‐function mechanism ([PMID:27294265]). Rescue experiments restoring wild-type RRAGA normalized mTORC1 signaling, further validating causality.

No conflicting reports have emerged disputing the association between RRAGA and autosomal dominant cataract; no alternative phenotypes have been ascribed to these alleles in the literature.

Together, genetic and experimental data support a moderate level of clinical validity for RRAGA in autosomal dominant cataract. Further replication across diverse populations and long-term natural history studies would solidify the association. Key take-home: RRAGA testing should be considered in early‐onset cataract cases, and mTORC1 modulation represents a promising therapeutic target.

References

• PLoS Genetics • 2016 • Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts PMID:27294265

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