84: NR6A1 and a newly described oculo‑vertebral‑renal (OVR) syndrome

Nature Communications - Genome sequencing identified rare NR6A1 variants in families with colobomatous microphthalmia, missing vertebrae and congenital kidney anomalies. In silico modeling, cell assays, and zebrafish knockdown/rescue experiments support pathogenicity and define NR6A1 as a pleiotropic developmental regulator. Key terms: NR6A1, coloboma, microphthalmia, vertebral anomalies, kidney anomalies.

Study Highlights:
Rare heterozygous NR6A1 variants were found in six independent families presenting coloboma/microphthalmia with missing vertebrae and some kidney anomalies, consistent with an autosomal dominant OVR syndrome with incomplete penetrance. Molecular modeling predicted disruption of DNA or intramolecular contacts, and two missense variants caused abnormal subcellular localization in HEK293 cells. Knockdown of zebrafish nr6a1a/nr6a1b produced eye, kidney, and somite defects that were rescued by wild‑type human NR6A1 mRNA but not by disease variants. NR6A1 is enriched in fetal ocular tissues and correlates with other coloboma genes, supporting a developmental role.

Conclusion:
NR6A1 variants cause a syndromic form of colobomatous microphthalmia with vertebral and renal anomalies (OVR syndrome); NR6A1 should be considered in genetic evaluation of MAC with associated skeletal or renal findings.

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Article title:
Variants in NR6A1 cause a novel oculo vertebral renal syndrome

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60574-y

Reference:
https://doi.org/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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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections discuss NR6A1 variants, the two pathogenic missense variants (R92W, R436C), their distinct molecular mechanisms, in vivo zebrafish validation with rescue experiments, and the clinical implication of NR6A1 as an OVR syndrome gene; also covers the genome-first approach and phenotype spectrum.
- transcript topics: NR6A1 and oculo-vertebral-renal (OVR) syndrome; NR6A1 variants R92W and R436C functional consequences; DNA-binding disruption at R92W; Cytoplasmic mislocalization at R436C; Zebrafish nr6a1a/nr6a1b knockdown and mRNA rescue experiments; Genome-first approach (UK100K Genomes Project) and MAC/MA cohorts

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- 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 rare NR6A1 variants identified across two cohorts (NEI coloboma/OVR and UK100KGP MAC) supporting autosomal dominant OVR syndrome.
- Missense variants R92W and R436C cause distinct functional defects (DNA-binding disruption for R92W; cytoplasmic retention for R436C).
- Zebrafish nr6a1a/nr6a1b knockdown recapitulates ocular, vertebral, and renal phenotypes; wild‑type NR6A1 mRNA rescues, but R92W/R436C variants do not.
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