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AGBL1 – Fuchs' Endothelial Dystrophy

Initial mapping in a three-generation family with 12 affected individuals and three unaffected identified a nonsense allele in AGBL1 that segregated with autosomal dominant late-onset Fuchs' endothelial dystrophy ( PMID:24094747 ). Sequencing of additional unrelated FECD cases revealed the same premature termination variant and three cases with a second missense mutation, c.3044G>C (p.Cys1015Ser), supporting a role for AGBL1 haploinsufficiency in disease pathogenesis ( PMID:24094747 ). Functional assays demonstrated that the truncated AGBL1 protein mislocalizes to the nucleus and diminishes its biochemical interaction with TCF4, a known FECD factor ( PMID:24094747 ).

More recent systematic and expression studies have challenged this association. Transcriptomic analyses failed to detect AGBL1 expression in normal or FECD corneal endothelia, and carriers of previously reported AGBL1 variants showed no FECD phenotype on ophthalmologic examination ( PMID:40244234 , PMID:37441688 ). These findings undermine replication and functional expression evidence, casting doubt on the clinical validity of AGBL1 variant screening in FECD.

Key Take-home: Current evidence disputes AGBL1 as a causative gene for Fuchs' endothelial dystrophy; clinical testing is not warranted.

References

  • American journal of human genetics • 2013 • Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. PMID:24094747
  • International journal of molecular sciences • 2025 • From Genes to Disease: Reassessing LOXHD1 and AGBL1's Contribution to Fuchs' Dystrophy. PMID:40244234
  • Frontiers in medicine • 2023 • Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs' endothelial corneal dystrophy. PMID:37441688

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Initial segregation in a large AD pedigree and five unrelated cases ([PMID:24094747]) but subsequent expression and phenotyping studies failed to confirm a role ([PMID:37441688], [PMID:40244234]).

Genetic Evidence

Limited

One family with co-segregation in 12 individuals and five additional probands with AGBL1 variants ([PMID:24094747]); lack of replication in case-control and cohorts.

Functional Evidence

Limited

In vitro mislocalization and reduced TCF4 interaction for truncated AGBL1 ([PMID:24094747]), but transcriptome data show absent expression in corneal endothelium ([PMID:37441688]).