Peter J Kullar, Aurora Gomez-Duran, Payam A Gammage, Caterina Garone, Michal Minczuk, Zoe Golder, Janet Wilson, Julio Montoya, Sanna Häkli, Mikko Kärppä, Rita Horvath, Kari Majamaa, Patrick F Chinnery; Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family, Brain, Volume 141, Issue 1, 1 January 2018, Pages 55–62, https://doi.org/10.1093/brain/awx295
Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family
|Author:||Kullar, Peter J.1,2; Gomez-Duran, Aurora1,2; Gammage, Payam A.1;|
1MRC-Mitochondrial Biology Unit, University of Cambridge, CB2 0XY, UK
2Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK
3Institute of Health and Society, Newcastle University, Baddiley-Clark Building, Richardson Road, Newcastle upon Tyne, NE2 4AX, UK
4Universidad de Zaragoza-CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón, Spain
5Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland
6Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
7Institute of Genetic Medicine, Newcastle University, UK
|Online Access:||PDF Full Text (PDF, 0.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201803276200
Oxford University Press,
|Publish Date:|| 2018-03-27
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.
Brain. A journal of neurology
|Pages:||55 - 62|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
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).
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.