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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
In most cases, MRI of the brain reveals the classic ‘molar tooth sign’. Genetic testing is currently clinically available for four genes: AHI1 (JBTS3), NPHP1 (JBTS4), CEP290 (JBTS5), and TMEM67 (JBTS6). Together, however, these account for only about 30–40% of cases. Targeted exome-based panels are becoming available that target upward of 94 ciliopathy genes and are thus close to definitive.
Bardet−Biedl Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The identification of 21 genes involved in BBS (i.e., BBS1, BBS2, BBS3 [ARL6], BBS4, BBS5, BBS6 [MKKS], BBS7, BBS8 [TTC8], BBS9, BBS10, BBS11 [TRIM32], BBS12, BBS13 [MKS1], BBS14 [CEP290], BBS15 [WDPCP], BBS16 [SDCCAG8], BBS17 [LZTFL1], BBS18 [BBIP1], BBS19 [IFT27], BBS20 [IFT72], and BBS21 [C8ORF37/NPHP1]) through linkage analysis and other approaches have revealed important insights on the pathogenesis of this clinically and genetically heterogeneous ciliopathy [8–10].
An overview of human pluripotent stem cell applications for the understanding and treatment of blindness
Published in John Ravenscroft, The Routledge Handbook of Visual Impairment, 2019
Louise A. Rooney, Duncan E. Crombie, Grace E. Lidgerwood, Maciej Daniszewski, Alice Pébay
Retinal organoids (optic cups) are also very useful for disease modelling as they can be used for phenotypic screening in retinal dystrophies and optic neuropathies, to interrogate interactions between RPE, photoreceptors or RGCs, providing a model to study interactions of the various cell layers within the neural retina. Hence, it can be used as a tool to model development and degenerative diseases of the retina and optic nerve. Once key phenotypes will have been identified, those can become a screening outcome in the search of treatments to counteract these pathological processes. The potential of optic cups for disease modelling and screening of novel therapies was recently described in (Parfitt et al., 2016). Researchers demonstrated that the common mutation CEP290 responsible for Leber congenital amaurosis induced a cilia defect in photoreceptors within the optic cup obtained from patient-derived iPSCs, and described how treating optic cups with an antisense nucleotide restored CEP290 and cilia functions in the photoreceptors.
Clinical characteristics, imaging findings, and genetic results of a patient with CEP290-related cone-rod dystrophy
Published in Ophthalmic Genetics, 2021
Ferran Vilaplana, Andrea Ros, Belen Garcia, Ignacio Blanco, Elisabeth Castellanos, Nicholas John Edwards, Xavier Valldeperas, Susana Ruiz-Bilbao, Antonio Sabala
CEP290 plays an important role in centrosome and cilia structures. These contribute to different cellular functions such as motility, transport and signal transduction. The phenotypic spectrum of its pathogenic variants ranges from localized diseases of the eye to major syndromes with systemic involvement (7). The wide range of phenotypes associated with CEP290 may be explained by the presence of cilia in the whole body (8). The mechanism underlying this variable phenotype is not well understood. To date, the health conditions related to CEP290 mutations that have been described are (LCA), early onset severe retinal dystrophy, retinitis pigmentosa, cone dystrophy, Bardet–Biedl syndrome, Joubert syndrome, Meckel syndrome, and Senior-Loken syndrome. Most cases had symptoms starting at birth. Late-onset in adulthood was described in a few patients with isolated retinitis pigmentosa and a case of cone dystrophy (2). These cases do not differ in the age-of-onset from the patient reported herein.
Investigation of CEP290 genotype-phenotype correlations in a patient with retinitis pigmentosa, infertility, end-stage renal disease, and a novel mutation
Published in Ophthalmic Genetics, 2020
Madeline Williamson, Elias Traboulsi, Meghan DeBenedictis
There is no consensus view that explains why mutations in a single gene, such as CEP290, result in such varied disease phenotypes. It was recently proposed that disease severity correlates with total protein levels of CEP290. In a process known as nonsense-mediated alternative splicing (NAS), exons harboring nonsense mutations are selectively skipped from the final transcript. Alternatively, the mutation harboring exons in CEP290 may be spliced by basal exon skipping. In either case, the result is increased expression of higher-functioning gene transcripts due to nonsense-mediated decay of the transcripts containing the premature stop codons (14). Whether the process is better described as NAS or basal exon skipping is irrelevant to the fact that therapies utilizing alternative splicing to exclude exons containing nonsense mutations could be of great benefit to patients and warrants further investigation (15). However, alternative splicing and compensatory expression of functioning gene products cannot explain the difference in phenotypes of patients with identical genotypes, such as those homozygous for the c.4723A>T mutation. One possible explanation for the additional variation in phenotype severity would be existence of modifying variants in other genes involved in the pathway of proper cilia function (16).
A novel CEP290 disease-causing variant identified in a patient with leber congenital amaurosis using a medical diagnostic panel sequencing
Published in Ophthalmic Genetics, 2022
Bin-Bin Chen, Yi Zhai, Ya-Nan Huo, Shuo Yang, Zhi-Yong Zhang
CEP290 protein is a centrosomal protein of 2479 amino acids with a molecular weight of 290 kDa. It was first identified in a proteomic analysis of the human centrosome. The protein is strongly conserved throughout evolution and contains several predicted motifs (15). The CEP290 protein is expressed in the centrosome of dividing cells, the nucleus, and the basal bodies of the primary cilia in many cell types, such as photoreceptor (16). Ultrastructural analysis has shown that the CEP290 protein resides at Y-link junctions of the ciliary transition zone and stabilizes the linkage of axoneme microtubules to the ciliary membrane (17).