Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination

Coppieters, Frauke and Ascari, Giulia and Dannhausen, Katharina and Nikopoulos, Konstantinos and Peelman, Frank and Karlstetter, Marcus and Xu, Mingchu and Brachet, Cécile and Meunier, Isabelle and Tsilimbaris, Miltiadis K. and Tsika, Chrysanthi and Blazaki, Styliani V. and Vergult, Sarah and Farinelli, Pietro and Van Laethem, Thalia and Bauwens, Miriam and De Bruyne, Marieke and Chen, Rui and Langmann, Thomas and Sui, Ruifang and Meire, Françoise and Rivolta, Carlo and Hamel, Christian P. and Leroy, Bart P. and De Baere, Elfride. (2016) Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. American Journal of Human Genetics, 99 (2). pp. 470-480.

[img] PDF - Published Version
Available under License CC BY-NC-ND (Attribution-NonCommercial-NoDerivatives).


Official URL: https://edoc.unibas.ch/81703/

Downloads: Statistics Overview


Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
edoc DOI:
Last Modified:02 Mar 2021 14:40
Deposited On:02 Mar 2021 14:40

Repository Staff Only: item control page