Pathogenic MYRF ICA Domain Variant is Aberrantly Trafficked in the RPE and Results in Isolated Nanophthalmos

MYRF p.R695C (c.2083C>T) is pathogenic for isolated nanophthalmos and causes mild retinal pigment epithelial disruption, with cleavage deficiency and apical mislocalization in human RPE cells.

• Why it matters: The study addresses how a specific MYRF ICA domain variant produces a gene-dosage–dependent clinical spectrum, and what molecular mechanism links MYRF dysfunction to eye growth defects.
• What they did: Using whole genome sequencing plus Ensembl VEP and PyMOL modeling, the authors tested FLAG-tagged MYRF p.R695C in human primary RPE and/or ARPE-19 cells for transcriptional activity, localization, cleavage, and trafficking.
• The result: In HEK293T co-expression assays, p.R695C showed reduced synergistic transcriptional activity with SOX10, and trafficking experiments indicated wildtype MYRF reaches the apical surface/plasma membrane while endogenous MYRF needs ER-to-Golgi pathways for nuclear localization and cleavage dynamics.

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