title: Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination.
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.
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium; pxlence BVBA, 9200 Dendermonde, Belgium. Electronic address: frauke.coppieters@ugent.be.
authors.forename: Frauke
authors.initials: F
authors.lastname: Coppieters
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ascari
authors.affiliation: Department of Ophthalmology, University of Cologne, 50931 Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dannhausen
authors.affiliation: Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Nikopoulos
authors.affiliation: Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.affiliation: Department of Ophthalmology, University of Cologne, 50931 Cologne, Germany; Therapeutic Research Group Ophthalmology, Bayer Pharma AG, 42096 Wuppertal, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Pediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1000 Brussels, Belgium.
authors.forename: Cécile
authors.initials: C
authors.lastname: Brachet
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.affiliation: Department of Ophthalmology, Medical School, University of Crete, 71409 Heraklion, Greece.
authors.forename: Miltiadis K
authors.initials: MK
authors.lastname: Tsilimbaris
authors.affiliation: Department of Ophthalmology, Medical School, University of Crete, 71409 Heraklion, Greece.
authors.forename: Chrysanthi
authors.initials: C
authors.lastname: Tsika
authors.affiliation: Department of Ophthalmology, Medical School, University of Crete, 71409 Heraklion, Greece.
authors.forename: Styliani V
authors.initials: SV
authors.lastname: Blazaki
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vergult
authors.affiliation: Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Pietro
authors.initials: P
authors.lastname: Farinelli
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Thalia
authors.initials: T
authors.lastname: Van Laethem
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bauwens
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Marieke
authors.initials: M
authors.lastname: De Bruyne
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, University of Cologne, 50931 Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 100730 Beijing, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
authors.affiliation: Department of Ophthalmology, Hôpital Universitaire des Enfants Reine Fabiola, 1000 Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Meire
authors.affiliation: Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: 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.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: 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.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: elfride.debaere@ugent.be.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002648:Child; D003241:Consanguinity; D044842:Cullin Proteins / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D012160:Retina / Q000378:metabolism; D058499:Retinal Dystrophies / Q000235:genetics*; D013577:Syndrome; D014421:Turkey; D054875:Ubiquitination / Q000235:genetics*
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; D020662:Guanine Nucleotide Exchange Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C482643:RCBTB1 protein, human; D012333:RNA, Messenger