306: SAXO6 loss-of-function in photoreceptor cilia links a microtubule inner protein to late-onset retinal dystrophy

Moye AR et al., The American Journal of Human Genetics - Biallelic loss-of-function variants in SAXO6, a microtubule inner protein of photoreceptor cilia, cause late-onset retinal dystrophy by destabilizing axonemal microtubules. Key terms: SAXO6, microtubule inner protein, photoreceptor cilia, retinal dystrophy, iU-ExM.

Study Highlights:
The study analyzed human patients with late-onset recessive retinal dystrophy and combined genetic sequencing (WES/WGS and long-read RNA) with high-resolution imaging and proteomics. Iterative ultrastructure expansion microscopy and immuno-gold TEM localized SAXO6 to specific microtubule doublets in photoreceptor connecting cilia and outer segments and to motile cilia in airway models. Cross-linking mass spectrometry on isolated bovine tracheal cilia detected an interaction between SAXO6 Mn-motif regions and α-tubulin (Lys370), supporting SAXO6 as a microtubule inner protein. Functionally, predicted null SAXO6 genotypes segregate with late-onset RP or cone-rod dystrophy, implicating MIP dysfunction in long-term photoreceptor stability.

Conclusion:
Biallelic loss-of-function variants in SAXO6 cause late-onset retinal dystrophy, likely by disrupting a microtubule inner protein that stabilizes photoreceptor axonemes.

Music:
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Article title:
Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, cause a late-onset retinal dystrophy

First author:
Moye AR

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.02.001

Reference:
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, cause a late-onset retinal dystrophy. The American Journal of Human Genetics. 2026 Mar 5;113:1–18. https://doi.org/10.1016/j.ajhg.2026.02.001

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering SAXO6 gene discovery and renaming from MDM1; SAXO6 LOF variants and segregation; SAXO6 localization in photoreceptor cilia and motile cilia; imaging methods iU-ExM and Ig-TEM; cross-linking MS evidence for SAXO6–α-tubulin interaction; rod vs cone MT doublet occupancy; clinical impli
- transcript topics: SAXO6 gene discovery and renaming from MDM1; Bi-allelic SAXO6 LOF variants and family segregation; Subcellular localization of SAXO6 in photoreceptor cilia (CC/OS) and in motile cilia; Imaging methods: iterative ultrastructure expansion microscopy (iU-ExM); Immuno-gold TEM localization of SAXO6; Cross-linking mass spectrometry evidence for SAXO6–α-tubulin interaction

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Six individuals from five families carry bi-allelic SAXO6 loss-of-function variants associated with late-onset RP/CRD
- SAXO6 renamed from MDM1 to SAXO6 (stabilizer of axonemal microtubules 6)
- SAXO6 localizes inside the lumen of photoreceptor ciliary microtubules and in motile cilia
- Cross-linking MS identifies an interaction between SAXO6 (Lys201) and α-tubulin (Lys370) with ~30 Å separation
- Iterative ultrastructure expansion microscopy expanded tissue ~10×, revealing SAXO6 localization along microtubule doublets
- Rods show SAXO6 occupancy on 6–7 microtubule doublets; cones on all 9 doublets

QC result: Pass.