SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance.
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Authors
Jurkute, Neringa
D'Esposito, Fabiana
Robson, Anthony G
Pitceathly, Robert DS
Cordeiro, Francesca
Raymond, F Lucy
Moore, Anthony T
Michaelides, Michel
Yu-Wai-Man, Patrick
Webster, Andrew R
Arno, Gavin
Genomics England Research Consortium
Publication Date
2021-12-01Journal Title
Invest Ophthalmol Vis Sci
ISSN
0146-0404
Publisher
Association for Research in Vision and Ophthalmology (ARVO)
Volume
62
Issue
15
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Jurkute, N., D'Esposito, F., Robson, A. G., Pitceathly, R. D., Cordeiro, F., Raymond, F. L., Moore, A. T., et al. (2021). SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance.. Invest Ophthalmol Vis Sci, 62 (15) https://doi.org/10.1167/iovs.62.15.12
Description
Funder: Wellcome Trust
Abstract
PURPOSE: To report novel genotypes and expand the phenotype spectrum of SSBP1-disease and explore potential disease mechanism. METHODS: Five families with previously unsolved optic atrophy and retinal dystrophy underwent whole genome sequencing as part of the National Institute for Health Research BioResource Rare-Diseases and the UK's 100,000 Genomes Project. In silico analysis and protein modelling was performed on the identified variants. Deep phenotyping including retinal imaging and International Society for Clinical Electrophysiology of Vision standard visual electrophysiology was performed. RESULTS: Seven individuals from five unrelated families with bilateral optic atrophy and/or retinal dystrophy with extraocular signs and symptoms in some are described. In total, 6 SSBP1 variants were identified including the previously unreported variants: c.151A>G, p.(Lys51Glu), c.335G>A p.(Gly112Glu), and c.380G>A, p.(Arg127Gln). One individual was found to carry biallelic variants (c.380G>A p.(Arg127Gln); c.394A>G p.(Ile132Val)) associated with likely autosomal recessive SSBP1-disease. In silico analysis predicted all variants to be pathogenic and Three-dimensional protein modelling suggested possible disease mechanisms via decreased single-stranded DNA binding affinity or impaired higher structure formation. CONCLUSIONS: SSBP1 is essential for mitochondrial DNA replication and maintenance, with defects leading to a spectrum of disease that includes optic atrophy and/or retinal dystrophy, occurring with or without extraocular features. This study provides evidence of intrafamilial variability and confirms the existence of an autosomal recessive inheritance in SSBP1-disease consequent upon a previously unreported genotype.
Keywords
Humans, Optic Atrophy, Mitochondrial Diseases, DNA-Binding Proteins, Mitochondrial Proteins, DNA, Mitochondrial, Electroretinography, Pedigree, Amino Acid Sequence, Molecular Conformation, Protein Structure, Quaternary, Genes, Recessive, Penetrance, Mutation, Missense, Molecular Sequence Data, Adolescent, Middle Aged, Child, Preschool, Female, Male, Protein Stability, Retinal Dystrophies, Genotyping Techniques, Whole Genome Sequencing
Sponsorship
National Institute for Health Research (IS-BRC-1215-20014)
Identifiers
34905022, PMC8684315
External DOI: https://doi.org/10.1167/iovs.62.15.12
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333270
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