Deep clinical phenotyping and gene expression analysis in a patient with RCBTB1-associated retinopathy

Background: Mutations in the RCC1 and BTB domain-containing protein 1 (RCBTB1) gene have been implicated in a rare form of retinal dystrophy. Herein, we report the clinical features of a 45-year-old Singaporean-Chinese female and her presymptomatic sibling, who each possesses compound heterozygous mutations in RCBTB1. Expression of RCBTB1 in patient-derived cells was evaluated.Materials and Methods: The natural history was documented by a series of ophthalmic examinations including electroretinography, fundus autofluorescence imaging, spectral-domain optical coherence tomography, visual field, microperimetry, and adaptive optics retinal imaging. Patient DNA was genetically analysed using a 537-gene Next Generation Sequencing panel and targeted Sanger sequencing. Expression of RCBTB1 in lymphocytes, fibroblasts, and induced pluripotent stem cells (iPSC) derived from the proband and healthy controls was characterized by quantitative PCR, Sanger sequencing, and western blotting.Results: The proband presented with left visual distortion at age 40 due to extrafoveal chorioretinal atrophy. Atrophy expanded at 1.3 (OD) and 1.0 (OS) mm2/year. Total macular volume declined by 0.09 (OD) and 0.13 (OS) mm3/year. Microperimetry demonstrated enlarging scotoma in both eyes. Generalised cone dysfunction was demonstrated by electroretinography. A retinal dystrophy panel testing revealed biallelic frameshifting mutations, c.170delG (p.Gly57Glufs*12) and c.707delA (p.Asn236Thrfs*11) in RCBTB1. The level of RCBTB1 mRNA expression was reduced in patient-derived lymphocytes compared to controls. RCBTB1 protein was detected in control fibroblasts and iPSC but was absent in patient-derived cells.Conclusions: Atrophy expansion rate and macular volume change are feasible endpoints for monitoring RCBTB1-associated retinopathy. We provide further functional evidence of pathogenicity for two disease-causing variants using patient-derived iPSCs.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:42

Enthalten in:

Ophthalmic genetics - 42(2021), 3 vom: 01. Juni, Seite 266-275

Sprache:

Englisch

Beteiligte Personen:

Huang, Zhiqin [VerfasserIn]
Zhang, Dan [VerfasserIn]
Thompson, Jennifer A [VerfasserIn]
Jamuar, Saumya S [VerfasserIn]
Roshandel, Danial [VerfasserIn]
Jennings, Luke [VerfasserIn]
Mellough, Carla [VerfasserIn]
Charng, Jason [VerfasserIn]
Chen, Shang-Chih [VerfasserIn]
McLaren, Terri L [VerfasserIn]
Lamey, Tina M [VerfasserIn]
Chelva, Enid [VerfasserIn]
De Roach, John N [VerfasserIn]
Chan, Choi Mun [VerfasserIn]
McLenachan, Samuel [VerfasserIn]
Chen, Fred K [VerfasserIn]

Links:

Volltext

Themen:

Guanine Nucleotide Exchange Factors
Inherited retinal disease
Journal Article
RCBTB1
RCBTB1 protein, human
RNA, Messenger
Research Support, Non-U.S. Gov't
Retinal pigment epithelium

Anmerkungen:

Date Completed 31.12.2021

Date Revised 07.12.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1080/13816810.2021.1891551

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM321828879