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Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood  F.-Nora Vögtle,

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Presentation on theme: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood  F.-Nora Vögtle,"— Presentation transcript:

1 Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood  F.-Nora Vögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A. Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu, Deepali N. Shinde, Ulrich Stephani, Johan L.K. Van Hove, Franz-Josef Müller, Ingo Helbig  The American Journal of Human Genetics  Volume 102, Issue 4, Pages (April 2018) DOI: /j.ajhg Copyright © 2018 American Society of Human Genetics Terms and Conditions

2 Figure 1 Genetics and MRI of Individuals Carrying PMPCB Variants
(A) Pedigrees of all families with PMPCB pathogenic variants. Black symbols designate affected individuals. (B) Sagittal T1 MRI images of individual A:II-1 at 13 months (a), individual B:II-2 at 4 years (b), individual C:II-1 at 3 years (c), and individual D:II-1 at 3 years 3 months (d) demonstrating cerebellar atrophy in all four individuals. T2 transverse images of individual D:II-1 at 1 year (e) and 4 years 7 months (g) and individual D:II-2 at 9 months (f) and 3 years, 3 months (h), demonstrating progressive cerebral atrophy. (C) Model of the crystal structure of the yeast MPP heterodimer (Mas1, blue; Mas2, gray) with the bound presequence peptide (green) in front (left) and back (right) view. The active site (yellow) and the positions of the mutations (red) are shown in stick representation. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

3 Figure 2 Analysis of Mitochondria Isolated from PMPCB iPSCs and Dermal Fibroblasts (A) Morphology and ICC-based characterization of hiPSC clone D:II-2.11 derived from affected individual D:II-2. BF, bright field. (B) Protein steady-state levels of mitochondria isolated from three different PMPCB iPSC cell clones (D:II-2.4, D:II-2.9, D:II-2.11) and controls (Ctrl.). i, intermediate; m, mature. (C) Quantifications of protein steady-state levels from (B). Values represent mean ± SEM (error bars; n = 3). (D) Protein steady-state analysis of mitochondria isolated from fibroblasts of family D with affected individual D:II-2 and individual A:II-1 and controls (Ctrl. 1–3). (E) Processing of radiolabeled Frataxin (FXN) precursor in mitochondrial extract from affected individual D:II-2 (D:II-2.4) and control (Ctrl., C2.2) iPSC line. α-GRP75, loading control. (F) Formation of ISD complex in mitochondria isolated from control (C1, C2.2, C2.5) and affected individual (D:II-2.4, D:II-2.9, D:II-2.11) hiPSC lines. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

4 Figure 3 Analysis of PMPCB Mutations in Yeast
(A) Growth of Mas1 wild-type, Mas1Arg144Cys, and Mas1Thr170Pro mutant yeast strains under fermentative and respiratory conditions. (B) Import of radiolabelled precursors upon in organello heat shock into mitochondria isolated from wild-type and Mas1 mutant cells. p, precursor; i, intermediate; m, mature. (C) Western blot analysis of steady-state protein levels in Mas1 wild-type, Mas1Arg144Cys, and Mas1Thr170Pro mutant mitochondria isolated after in vivo heat shock. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

5 Figure 4 Characterization of Mitochondrial Functions in Mas1 Mutant Yeast Cells (A) BN-PAGE analysis of respiratory chain complexes in Mas1 wild-type and mutant mitochondria isolated after cell growth at 23°C. (B) Analysis as in (A), mitochondria were isolated after in vivo heat shock. (C) Membrane potential measurement in mitochondria isolated from Mas1, Mas1Arg144Cys, and Mas1Thr170Pro cells after growth at permissive temperature (− heat shock; values represent mean ± SEM, n = 4) or in vivo heat shock (+ heat shock; values represent mean ± SEM, n = 3). (D) ISD complex formation in Mas1 wild-type and mutant mitochondria isolated at 23°C (− heat shock) or after in vivo heat shock. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

6 Figure 5 Analysis of Enzymatic Activity of Fe-S-Cluster-Containing Proteins and Protein Complexes in PMPCB Tissues (A) Isolated mitochondrial membrane fractions of individual A:II-1 and control (Ctrl.) muscle samples were analyzed by BN-PAGE followed by in-gel activity staining for respiratory chain complex I, II, IV, and V. (B) Assembly of respiratory chain complex I by BN-PAGE analysis in isolated mitochondrial membrane fractions obtained from affected individual A:II-1 and control fibroblasts. holocomplex, fully assembled complex I; ∗, lower molecular weight subcomplexes. (C) Enzymatic activity of mitochondrial and cytosolic aconitase in fibroblasts of individual A:II-1 and control. Values represent mean ± SD (error bars; control n = 9, A:II-1 n = 5). (D) Mitochondrial and cytosolic aconitase activity in muscle homogenates from individual A:II-1 and controls. Data are represented as mean ± SD (error bars; control n = 11, A:II-1 average of two measurements). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

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