Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitocho...

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Veröffentlicht in:Mitochondrion 2017-11, Vol.37, p.46-54
Hauptverfasser: Schottmann, Gudrun, Picker-Minh, Sylvie, Schwarz, Jana Marie, Gill, Esther, Rodenburg, Richard J T, Stenzel, Werner, Kaindl, Angela M, Schuelke, Markus
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container_end_page 54
container_issue
container_start_page 46
container_title Mitochondrion
container_volume 37
creator Schottmann, Gudrun
Picker-Minh, Sylvie
Schwarz, Jana Marie
Gill, Esther
Rodenburg, Richard J T
Stenzel, Werner
Kaindl, Angela M
Schuelke, Markus
description Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial complex I and pyruvate dehydrogenase complex (PDHc) deficiency. Whole exome sequencing uncovered a known EXOSC3 mutation p.(D132A) as the underlying cause. In patient fibroblasts, a large portion of the EXOSC3 protein was trapped in the cytosol. MtDNA copy numbers in muscle were reduced to 35%, but mutations in the mtDNA and in nuclear mitochondrial genes were ruled out. RNA-Seq of patient muscle showed highly increased mRNA copy numbers, especially for genes encoding structural subunits of OXPHOS complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.
doi_str_mv 10.1016/j.mito.2017.06.007
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subjects Electron Transport Complex I - deficiency
Exosome Multienzyme Ribonuclease Complex - genetics
Humans
Infant
Male
Mitochondrial Diseases - genetics
Mitochondrial Diseases - pathology
Mutation
Olivopontocerebellar Atrophies - genetics
Olivopontocerebellar Atrophies - pathology
Pyruvate Dehydrogenase Complex Deficiency Disease
RNA-Binding Proteins - genetics
title Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia
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