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

TitleIsolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination.
Publication TypeJournal Article
Year of Publication2016
AuthorsCoppieters, F, Ascari, G, Dannhausen, K, Nikopoulos, K, Peelman, F, Karlstetter, M, Xu, M, Brachet, C, Meunier, I, Tsilimbaris, MK, Tsika, C, Blazaki, SV, Vergult, S, Farinelli, P, Van Laethem, T, Bauwens, M, De Bruyne, M, Chen, R, Langmann, T, Sui, R, Meire, F, Rivolta, C, Hamel, CP, Leroy, BP, De Baere, E
JournalAm J Hum Genet
Date Published2016 Aug 04
KeywordsAdolescent, Adult, Age of Onset, Alleles, Child, Consanguinity, Cullin Proteins, Exome, Female, Founder Effect, Genes, Recessive, Guanine Nucleotide Exchange Factors, Haplotypes, Homozygote, Humans, Lymphocytes, Male, Mutation, Missense, NF-E2-Related Factor 2, Pedigree, Phenotype, Retina, Retinal Dystrophies, RNA, Messenger, Syndrome, Turkey, Ubiquitination

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.

Alternate JournalAm J Hum Genet
PubMed ID27486781
PubMed Central IDPMC4974088
Grant ListP30 EY002520 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
S10 RR026550 / RR / NCRR NIH HHS / United States

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