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

Détails

Ressource 1Télécharger: BIB_D94870497C06.P001.pdf (1673.38 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_D94870497C06
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination.
Périodique
American journal of human genetics
Auteur⸱e⸱s
Coppieters F., Ascari G., Dannhausen K., Nikopoulos K., Peelman F., Karlstetter M., Xu M., Brachet C., Meunier I., Tsilimbaris M.K., Tsika C., Blazaki S.V., Vergult S., Farinelli P., Van Laethem T., Bauwens M., De Bruyne M., Chen R., Langmann T., Sui R., Meire F., Rivolta C., Hamel C.P., Leroy B.P., De Baere E.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
04/08/2016
Peer-reviewed
Oui
Volume
99
Numéro
2
Pages
470-480
Langue
anglais
Notes
Publication types: Case Reports ; Journal Article
Publication Status: ppublish
Résumé
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.

Mots-clé
Adolescent, Adult, Age of Onset, Alleles, Child, Consanguinity, Cullin Proteins/metabolism, Exome/genetics, Female, Founder Effect, Genes, Recessive, Guanine Nucleotide Exchange Factors/genetics, Haplotypes/genetics, Homozygote, Humans, Lymphocytes/metabolism, Male, Mutation, Missense/genetics, NF-E2-Related Factor 2/metabolism, Pedigree, Phenotype, RNA, Messenger/genetics, Retina/metabolism, Retinal Dystrophies/genetics, Syndrome, Turkey, Ubiquitination/genetics
Pubmed
Open Access
Oui
Création de la notice
04/08/2016 16:34
Dernière modification de la notice
20/08/2019 15:58
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