Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, cause 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 that affect the survival and function of rod and cone photoreceptors and, in most instances, lead to progressive visual loss. Yet some affected individuals 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 bi-allelic 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 cilium 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 α-tubulin, supporting its classification as a microtubule inner protein (MIP). These results link SAXO proteins to Mendelian conditions, highlighting the fundamental role for MIPs in the preservation of long-term retinal function.