Zhiqin Huang1,2, Dan Zhang1,2, Jennifer A Thompson3,4, Saumya S Jamuar5,6,7, Danial Roshandel1,2, Luke Jennings2, Carla Mellough1,2, Jason Charng1,2, Shang-Chih Chen2, Terri L McLaren1,3,4, Tina M Lamey1,3,4, Enid Chelva4, John N De Roach1,3,4, Choi Mun Chan8, Samuel McLenachan1,2, Fred K Chen1,2,3,9,10. 1. Centre for Ophthalmology and Visual Science, the University of Western Australia, Perth, Western Australia, Australia. 2. Lions Eye Institute, Perth, Western Australia, Australia. 3. Australian Inherited Retinal Disease Registry and DNA Bank (AIRDR), Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. 4. Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. 5. Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore. 6. Paediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore. 7. SingHealth Duke-NUS Genomic Medicine Centre, Singapore. 8. Medical Retina Department, Singapore National Eye Centre, Singapore. 9. Department of Ophthalmology, Royal Perth Hospital, Perth, Western Australia, Australia. 10. Department of Ophthalmology, Perth Children's Hospital, Nedlands, Western Australia, Australia.
Abstract
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.
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.
Authors: Andrew J Catomeris; Brian G Ballios; Riccardo Sangermano; Naomi E Wagner; Jason I Comander; Eric A Pierce; Emily M Place; Kinga M Bujakowska; Rachel M Huckfeldt Journal: Ophthalmic Genet Date: 2022-01-20 Impact factor: 1.274
Authors: Zhiqin Huang; Dan Zhang; Shang-Chih Chen; Luke Jennings; Livia S Carvalho; Sue Fletcher; Fred K Chen; Samuel McLenachan Journal: J Cell Mol Med Date: 2021-10-07 Impact factor: 5.310