Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain.

von Alpen, Désirée; Tran, Hoai Viet; Guex, Nicolas; Venturini, Giulia; Munier, Francis L; Schorderet, Daniel F; Haider, Neena B; Escher, Pascal (2015). Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain. Human mutation, 36(6), pp. 599-610. Wiley-Blackwell 10.1002/humu.22775

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NR2E3 encodes the photoreceptor-specific nuclear hormone receptor that acts as a repressor of cone-specific gene expression in rod photoreceptors, and as an activator of several rod-specific genes. Recessive variants located in the ligand-binding domain (LBD) of NR2E3 cause enhanced short wavelength sensitive- (S-) cone syndrome (ESCS), a retinal degeneration characterized by an excess of S-cones and non-functional rods. We analyzed the dimerization properties of NR2E3 and the effect of disease-causing LBD missense variants by bioluminescence resonance energy transfer (BRET(2) ) protein interaction assays. Homodimerization was not affected in presence of p.A256V, p.R039G, p.R311Q, and p.R334G variants, but abolished in presence of p.L263P, p.L336P, p.L353V, p.R385P, and p.M407K variants. Homology modeling predicted structural changes induced by NR2E3 LBD variants. NR2E3 LBD variants did not affect interaction with CRX, but with NRL and rev-erbα/NR1D1. CRX and NRL heterodimerized more efficiently together, than did either with NR2E3. NR2E3 did not heterodimerize with TLX/NR2E1 and RXRα/NR2C1. The identification of a new compound heterozygous patient with detectable rod function, who expressed solely the p.A256V variant protein, suggests a correlation between LBD variants able to form functional NR2E3 dimers and atypical mild forms of ESCS with residual rod function.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology

UniBE Contributor:

Escher, Pascal

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1059-7794

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

PD Dr. Pascal Escher

Date Deposited:

10 Jul 2017 10:14

Last Modified:

31 Jul 2017 08:31

Publisher DOI:

10.1002/humu.22775

PubMed ID:

25703721

Uncontrolled Keywords:

NR2E3; genotype-phenotype correlation; photoreceptor development; retinal degeneration

BORIS DOI:

10.7892/boris.101771

URI:

https://boris.unibe.ch/id/eprint/101771

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