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

PJ Kullar, A Gomez-Duran, PA Gammage, C Garone… - Brain, 2018 - academic.oup.com
Brain, 2018academic.oup.com
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 …
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.
Oxford University Press