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

TitleHeterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.
Publication TypeJournal Article
Year of Publication2018
AuthorsKullar, PJ, Gomez-Duran, A, Gammage, PA, Garone, C, Minczuk, M, Golder, Z, Wilson, J, Montoya, J, Häkli, S, Kärppä, M, Horvath, R, Majamaa, K, Chinnery, PF
JournalBrain
Volume141
Issue1
Pagination55-62
Date Published2018 01 01
ISSN1460-2156
KeywordsAdolescent, Child, Child, Preschool, DNA Mutational Analysis, DNA-Binding Proteins, Electron Transport Complex II, Electron Transport Complex IV, Family Health, Female, Fibroblasts, Hearing Loss, Heterozygote, Humans, Infant, Male, Mitochondrial Diseases, Mitochondrial Proteins, Mitochondrial Proton-Translocating ATPases, Muscle, Skeletal, Mutation, Young Adult
Abstract

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.

DOI10.1093/brain/awx295
Alternate JournalBrain
Citation Key10.1093/brain/awx295
PubMed ID29182774
PubMed Central IDPMC5837410
Grant ListG0601943 / / Medical Research Council / United Kingdom
MC_U105697135 / / Medical Research Council / United Kingdom
MC_UP_1501/2 / / Medical Research Council / United Kingdom
101700/A/13/Z / / Wellcome Trust / United Kingdom
101876/Z/13/Z / / Wellcome Trust / United Kingdom
096919Z/11/Z / / Wellcome Trust / United Kingdom