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

Am J Hum Genet. 2016 Aug 4;99(2):470-80. doi: 10.1016/j.ajhg.2016.06.017.

Frauke Coppieters ¹, Giulia Ascari ², Katharina Dannhausen ³, Konstantinos Nikopoulos ⁴, Frank Peelman ⁵, Marcus Karlstetter ⁶, Mingchu Xu ⁷, Cécile Brachet ⁸, Isabelle Meunier ⁹, Miltiadis K Tsilimbaris ¹⁰, Chrysanthi Tsika ¹⁰, Styliani V Blazaki ¹⁰, Sarah Vergult ², Pietro Farinelli ⁴, Thalia Van Laethem ², Miriam Bauwens ², Marieke De Bruyne ², Rui Chen ¹¹, Thomas Langmann ³, Ruifang Sui ¹², Françoise Meire ¹³, Carlo Rivolta ⁴, Christian P Hamel ⁹, Bart P Leroy ¹⁴, Elfride De Baere ¹⁵

Affiliations

1 Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium; pxlence BVBA, 9200 Dendermonde, Belgium. Electronic address: [email protected].
2 Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
3 Department of Ophthalmology, University of Cologne, 50931 Cologne, Germany.
4 Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1011 Lausanne, Switzerland.
5 Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
6 Department of Ophthalmology, University of Cologne, 50931 Cologne, Germany; Therapeutic Research Group Ophthalmology, Bayer Pharma AG, 42096 Wuppertal, Germany.
7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
8 Pediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1000 Brussels, Belgium.
9 Genetic Sensory Diseases, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France; Université Montpellier, 34090 Montpellier, France; INSERM U1051, Institut des Neurosciences de Montpellier, 34091 Montpellier, France.
10 Department of Ophthalmology, Medical School, University of Crete, 71409 Heraklion, Greece.
11 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
12 Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 100730 Beijing, China.
13 Department of Ophthalmology, Hôpital Universitaire des Enfants Reine Fabiola, 1000 Brussels, Belgium.
14 Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium; Department of Ophthalmology, Ghent University Hospital and Ghent University, 9000 Ghent, Belgium; Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
15 Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: [email protected].

PMID: 27486781 DOI: 10.1016/j.ajhg.2016.06.017

Abstract

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.

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