Universität zu Köln

Coppieters, Frauke ORCID: 0000-0001-7224-0992, Ascari, Giulia ORCID: 0000-0001-6175-6774, Dannhausen, Katharina, Nikopoulos, Konstantinos ORCID: 0000-0002-1856-2752, Peelman, Frank, Karlstetter, Marcus, Xu, Mingchu, Brachet, Cecile ORCID: 0000-0001-7955-2534, Meunier, Isabelle, Tsilimbaris, Miltiadis K., Tsika, Chrysanthi, Blazaki, Styliani V., Vergult, Sarah ORCID: 0000-0002-0816-6262, Farinelli, Pietro ORCID: 0000-0002-4242-3090, Van Laethem, Thalia, Bauwens, Miriam, De Bruyne, Marieke ORCID: 0000-0001-6636-5537, Chen, Rui, Langmann, Thomas, Sui, Ruifang, Meire, Francoise, Rivolta, Carlo ORCID: 0000-0002-0733-9950, Hamel, Christian P., Leroy, Bart P. and De Baere, Elfride ORCID: 0000-0002-5609-6895 (2016). Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. Am. J. Hum. Genet., 99 (2). S. 470 - 481. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Coppieters, Frauke UNSPECIFIED orcid.org/0000-0001-7224-0992 UNSPECIFIED Ascari, Giulia UNSPECIFIED orcid.org/0000-0001-6175-6774 UNSPECIFIED Dannhausen, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikopoulos, Konstantinos UNSPECIFIED orcid.org/0000-0002-1856-2752 UNSPECIFIED Peelman, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Karlstetter, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Xu, Mingchu UNSPECIFIED UNSPECIFIED UNSPECIFIED Brachet, Cecile UNSPECIFIED orcid.org/0000-0001-7955-2534 UNSPECIFIED Meunier, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Tsilimbaris, Miltiadis K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tsika, Chrysanthi UNSPECIFIED UNSPECIFIED UNSPECIFIED Blazaki, Styliani V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vergult, Sarah UNSPECIFIED orcid.org/0000-0002-0816-6262 UNSPECIFIED Farinelli, Pietro UNSPECIFIED orcid.org/0000-0002-4242-3090 UNSPECIFIED Van Laethem, Thalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bauwens, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED De Bruyne, Marieke UNSPECIFIED orcid.org/0000-0001-6636-5537 UNSPECIFIED Chen, Rui UNSPECIFIED UNSPECIFIED UNSPECIFIED Langmann, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Sui, Ruifang UNSPECIFIED UNSPECIFIED UNSPECIFIED Meire, Francoise UNSPECIFIED UNSPECIFIED UNSPECIFIED Rivolta, Carlo UNSPECIFIED orcid.org/0000-0002-0733-9950 UNSPECIFIED Hamel, Christian P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leroy, Bart P. UNSPECIFIED UNSPECIFIED UNSPECIFIED De Baere, Elfride UNSPECIFIED orcid.org/0000-0002-5609-6895 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-266812
DOI:	10.1016/j.ajhg.2016.06.017
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	99
Number:	2
Page Range:	S. 470 - 481
Date:	2016
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DOMINANT RETINITIS-PIGMENTOSA; TRANSCRIPTION FACTOR NRF2; CONJUGATING ENZYME; EXPRESSION ANALYSIS; PROTEASOME SYSTEM; CHROMOSOME 13Q14; RESPONSE ELEMENT; PROTEIN; DISEASE; TOPORS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26681