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Loss of function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, causes a late-onset retinal dystrophy

ABSTRACT: Over 500 genes have been linked to various forms of inherited retinal diseases (IRDs), a class of Mendelian conditions affecting the survival and function of rod and cone photoreceptors and leading in most instances to progressive visual loss. Yet, some patients still lack a clear genetic diagnosis, suggesting that more disease-associated genes remain to be discovered. Following the genetic analysis of extended cohorts of individuals diagnosed with late-onset recessive retinal dystrophy, we identified biallelic combinations of six predicted null variants in MDM1 (now renamed SAXO6, stabilizer of axonemal microtubules 6) in six subjects from five families. Iterative ultrastructure expansion microscopy coupled with immuno-gold transmission electron microscopy revealed co-localization of SAXO6 with distinct ciliary microtubules from the immotile cilia present in rod and cone photoreceptors in human retina, as well as from the motile cilia present in lung epithelial cells. Cross-linking mass spectrometry uncovered an interaction between SAXO6 and alpha-tubulin, suggesting that SAXO6 is a microtubule inner protein, a component of the cilium that has never previously been linked to IRD. These results identify SAXO proteins in association with a Mendelian condition, highlighting the fundamental role of photoreceptor cilia in the preservation of retinal health.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Bos Taurus (ncbitaxon:9913)

SUBMITTER: Alexander Schmidt

PROVIDER: MSV000100624 | MassIVE | Wed Jan 28 08:30:00 GMT 2026

SECONDARY ACCESSION(S): PXD073717

REPOSITORIES: MassIVE

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