MassIVE MSV000100624

Partial Public PXD073717

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

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Description

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. [doi:10.25345/C5WH2DT83] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: inherited retinal diseases, retina, microtubule associated protein, connecting cilium, ciliopathy, retinitis pigmentosa, MDM1, SAXO, microtubule inner protein ; DatasetType:Proteomics

Contact

Principal Investigators:
(in alphabetical order) 		Alexander Schmidt, Biozentrum, Universtiy of Basel, 4056 Basel, Switzerland, N/A
Submitting User: verizy27

Publications

Moye AR, McCafferty CL, Lin S, Han JH, Dudakova L, Rodenburg K, Szabó V, Nagy ZZ, Zur D, Vajter M, Kousal B, Moulin AP, Graff-Meyer A, Roosing S, Mahroo OA, Arno G, Webster AR, Ben-Yosef T, Liskova P, Engel BD, Zobor D, Quinodoz M, Rivolta C.
Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, causes a late-onset retinal dystrophy.
Am J Hum Genet. Epub 2026 Feb 24.

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