Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family

Kullar, P. J. et al. (2018) Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family. Brain, 141(1), pp. 55-62. (doi: 10.1093/brain/awx295) (PMID:29182774) (PMCID:PMC5837410)

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The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.

Item Type:Articles
Additional Information:P.J.K. is a Wellcome Trust Clinical Research Training Fellow (101700/A/13/Z). P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease research (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. C.G. is supported by the European Commission under “Marie Skłodowska-Curie Actions”, Individual Fellowship – Reintegration Panel (Mitobiopath-705560). J.M. receives funding from the Instituto de Salud Carlos III (PI14/00005 and PI14/00070); Departamento de Ciencia, Tecnología y Universidad del Gobierno de Aragón (Grupos Consolidados B33) and FEDER Funding Program from the European Union; and Asociación de Enfermos de Patología Mitocondrial (AEPMI). P.A.G. and M.M. are supported by core funding from Medical Research Council (UK) (MC_U105697135).
Glasgow Author(s) Enlighten ID:Gammage, Dr Payam
Authors: Kullar, P. J., Gomez-Duran, A., Gammage, P. A., Garone, C., Minczuk, M., Golder, Z., Wilson, J., Montoya, J., Häkli, S., Kärppä, M., Horvath, R., Majamaa, K., and Chinnery, P. F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Brain
Publisher:Oxford University Press
ISSN (Online):1460-2156
Published Online:22 November 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Brain 141(1):55-62
Publisher Policy:Reproduced under a Creative Commons License

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