️ Episode 84: Variants in NR6A1 cause a novel oculo-vertebral-renal syndrome

In this episode of PaperCast Base by Base, we explore the discovery of rare variants in the orphan nuclear receptor gene NR6A1 as the genetic cause of a newly described autosomal dominant oculo-vertebral-renal (OVR) syndrome characterized by colobomatous microphthalmia, vertebral anomalies, and congenital kidney abnormalities.

Study Highlights:

We performed genome sequencing in six independent families affected by uveal coloboma with or without microphthalmia and identified six rare NR6A1 variants segregating with disease. Functional validation included in silico modeling predicting disrupted DNA binding and ligand domain interactions, cellular assays showing mislocalization of mutant NR6A1 isoforms, and zebrafish morpholino knockdown experiments demonstrating eye, kidney, and somite developmental defects. Rescue experiments in zebrafish confirmed that wild-type human NR6A1 mRNA restored normal development while pathogenic variants failed to rescue these phenotypes.

Conclusion:

This study establishes NR6A1 as a critical pleiotropic regulator of eye, vertebral, and renal development, expanding the molecular diagnostic framework for coloboma and related syndromes and opening paths for future functional and therapeutic research.

Reference:

Neelathi UM, Ullah E, George A, Maftei MI, Boobalan E, Sanchez-Mendoza D, Adams C, McGaughey D, Sergeev YV, AI Rawi R, Naik A, Bender C, Maumenee IH, Michaelides M, Tan TG, Lin S, Villasmil R, Blain D, Hufnagel RB, Arno G, Young RM, Guan B & Brooks BP. Variants in NR6A1 cause a novel oculo-vertebral-renal syndrome. Nat Commun. 2025;16:6111. doi:10.1038/s41467-025-60574-y

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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