Variants in NR6A1 cause a novel oculo vertebral renal syndrome

Uma M. Neelathi, Ehsan Ullah, Aman George, Mara I. Maftei, Elangovan Boobalan, Daniel Sanchez-Mendoza, Chloe Adams, David McGaughey, Yuri V. Sergeev, Ranya AI Rawi, Amelia Naik, Chelsea Bender, Irene H. Maumenee, Michel Michaelides, Tun Giap Tan, Siying Lin, Rafael Villasmil, Delphine Blain, Robert B. Hufnagel, Gavin Arno, Rodrigo M. Young, Bin Guan and Brian P. Brooks ()
Additional contact information
Uma M. Neelathi: National Institutes of Health
Ehsan Ullah: National Institutes of Health
Aman George: National Institutes of Health
Mara I. Maftei: University College London
Elangovan Boobalan: National Institutes of Health
Daniel Sanchez-Mendoza: National Institutes of Health
Chloe Adams: National Institutes of Health
David McGaughey: National Institutes of Health
Yuri V. Sergeev: National Institutes of Health
Ranya AI Rawi: National Institutes of Health
Amelia Naik: National Institutes of Health
Chelsea Bender: National Institutes of Health
Irene H. Maumenee: Columbia University
Michel Michaelides: University College London
Tun Giap Tan: Torbay and South Devon NHS Foundation Trust
Siying Lin: University College London
Rafael Villasmil: National Eye Institute
Delphine Blain: National Institutes of Health
Robert B. Hufnagel: National Institutes of Health
Gavin Arno: University College London
Rodrigo M. Young: University College London
Bin Guan: National Institutes of Health
Brian P. Brooks: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe an autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular, and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye, kidney, and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye, kidney, and vertebral development, and a pleiotropic gene responsible for OVR syndrome.

Date: 2025
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DOI: 10.1038/s41467-025-60574-y

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