PUBLICATION
Variants in NR6A1 cause a novel oculo vertebral renal syndrome
- Authors
- Neelathi, U.M., Ullah, E., George, A., Maftei, M.I., Boobalan, E., Sanchez-Mendoza, D., Adams, C., McGaughey, D., Sergeev, Y.V., Ai Rawi, R., Naik, A., Bender, C., Maumenee, I.H., Michaelides, M., Tan, T.G., Lin, S., Villasmil, R., Blain, D., Hufnagel, R.B., Arno, G., Young, R.M., Guan, B., Brooks, B.P.
- ID
- ZDB-PUB-250705-7
- Date
- 2025
- Source
- Nature communications 16: 61116111 (Journal)
- Registered Authors
- Brooks, Brian P., Hufnagel, Robert B., Maftei, Mara Ioana, Young, Rodrigo
- Keywords
- none
- MeSH Terms
-
- Adult
- Spine*/abnormalities
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Zebrafish/genetics
- Humans
- Pedigree
- Female
- Microphthalmos*/genetics
- Microphthalmos*/pathology
- Animals
- Coloboma*/genetics
- Male
- Kidney/abnormalities
- Eye
- PubMed
- 40610405 Full text @ Nat. Commun.
Citation
Neelathi, U.M., Ullah, E., George, A., Maftei, M.I., Boobalan, E., Sanchez-Mendoza, D., Adams, C., McGaughey, D., Sergeev, Y.V., Ai Rawi, R., Naik, A., Bender, C., Maumenee, I.H., Michaelides, M., Tan, T.G., Lin, S., Villasmil, R., Blain, D., Hufnagel, R.B., Arno, G., Young, R.M., Guan, B., Brooks, B.P. (2025) Variants in NR6A1 cause a novel oculo vertebral renal syndrome. Nature communications. 16:61116111.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping