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. ; Gomez-Duran, A. ; Gammage, P.A. ; Garone, C. ; Minczuk, M. ; Golder, Z. ; Wilson, J. ; Montoya, J. (Universidad de Zaragoza) ; Häkli, S. ; Kärppä, M. ; Horvath, R. ; Majamaa, K. ; Chinnery, P.F.

Resumen: 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.

Idioma: Inglés

DOI: 10.1093/brain/awx295

Año: 2018

Publicado en: Brain 141, 1 (2018), 55-62
ISSN: 0006-8950

Factor impacto JCR: 11.814 (2018)

Categ. JCR: NEUROSCIENCES rank: 11 / 266 = 0.041 (2018) - Q1 - T1
Categ. JCR: CLINICAL NEUROLOGY rank: 6 / 199 = 0.03 (2018) - Q1 - T1

Factor impacto SCIMAGO: 5.978 - Neurology (clinical) (Q1) - Medicine (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/FIS/PI14-00005
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI14-00070

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)