1. Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination
- Author
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Miltiadis K. Tsilimbaris, Elfride De Baere, Thomas Langmann, Styliani V. Blazaki, Cécile Brachet, Giulia Ascari, Konstantinos Nikopoulos, Sarah Vergult, Françoise Meire, Thalia Van Laethem, Christian P. Hamel, Mingchu Xu, Katharina Dannhausen, Frank Peelman, Marieke De Bruyne, Bart P. Leroy, Miriam Bauwens, Marcus Karlstetter, Carlo Rivolta, Ruifang Sui, Isabelle Meunier, Rui Chen, Frauke Coppieters, Pietro Farinelli, Chrysanthi Tsika, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
- Subjects
0301 basic medicine ,Male ,Génétique clinique ,Turkey ,TRANSCRIPTION FACTOR NRF2 ,PROTEIN ,030105 genetics & heredity ,medicine.disease_cause ,Consanguinity ,Medicine and Health Sciences ,CONJUGATING ENZYME ,Missense mutation ,Guanine Nucleotide Exchange Factors ,Exome ,Genetics(clinical) ,Lymphocytes ,Age of Onset ,Child ,Genetics (clinical) ,Genetics ,Mutation ,CHROMOSOME 13Q14 ,Homozygote ,EPITHELIAL-CELLS ,DOMINANT RETINITIS-PIGMENTOSA ,Syndrome ,Disease gene identification ,Cullin Proteins ,Founder Effect ,3. Good health ,Pedigree ,Phenotype ,Female ,PROTEASOME SYSTEM ,Biologie ,Adult ,Adolescent ,NF-E2-Related Factor 2 ,Mutation, Missense ,Genes, Recessive ,Biology ,Retina ,03 medical and health sciences ,Report ,Retinitis pigmentosa ,Retinal Dystrophies ,medicine ,Humans ,RNA, Messenger ,Allele ,Alleles ,CHRONIC LYMPHOCYTIC-LEUKEMIA ,RESPONSE ELEMENT ,Haplotype ,Ubiquitination ,Biology and Life Sciences ,medicine.disease ,Molecular biology ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Haplotypes ,Cullin Proteins/metabolism ,Exome/genetics ,Guanine Nucleotide Exchange Factors/genetics ,Haplotypes/genetics ,Lymphocytes/metabolism ,Mutation, Missense/genetics ,NF-E2-Related Factor 2/metabolism ,RNA, Messenger/genetics ,Retina/metabolism ,Retinal Dystrophies/genetics ,Ubiquitination/genetics ,EXPRESSION ANALYSIS ,Founder effect - 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., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2016
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