Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability Yair Anikster, Tobias B. Haack, Thierry Vilboux, Ben.

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Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability Yair Anikster, Tobias B. Haack, Thierry Vilboux, Ben Pode-Shakked, Beat Thöny, Nan Shen, Virginia Guarani, Thomas Meissner, Ertan Mayatepek, Friedrich K. Trefz, Dina Marek-Yagel, Aurora Martinez, Edward L. Huttlin, Joao A. Paulo, Riccardo Berutti, Jean-François Benoist, Apolline Imbard, Imen Dorboz, Gali Heimer, Yuval Landau, Limor Ziv-Strasser, May Christine V. Malicdan, Corinne Gemperle- Britschgi, Kirsten Cremer, Hartmut Engels, David Meili, Irene Keller, Rémy Bruggmann, Tim M. Strom, Thomas Meitinger, James C. Mullikin, Gerard Schwartz, Bruria Ben-Zeev, William A. Gahl, J. Wade Harper, Nenad Blau, Georg F. Hoffmann, Holger Prokisch, Thomas Opladen, Manuel Schiff The American Journal of Human Genetics Volume 100, Issue 2, Pages 257-266 (February 2017) DOI: 10.1016/j.ajhg.2017.01.002 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of the Investigated Families and Schematic Representation of the DNAJC12 Exon 4 Deletion (A) Pedigrees of four families with mutations in DNAJC12. The mutation status of affected (closed symbols) and healthy (open symbols) family members are noted. N.D., not determined. (B) Schematic representation of del6943 (c.298-968_503-2603del). Exome sequencing results (top) showing the alignment of sequencing reads to the reference genome for the controls and affected individuals (A-IV-2 and D-V-1), as visualized with the Integrative Genomics Viewer (IGV) tool. Breakpoint junction sequences (bottom) are shown, depicting the 6.943 kb deletion (del6943, c.298-968_503-2603del) containing exon 4. The breakpoint junction sequence (chromatogram) is aligned with reference sequences. The American Journal of Human Genetics 2017 100, 257-266DOI: (10.1016/j.ajhg.2017.01.002) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 DNAJC12 Expression Studies (A) DNAJC12 mRNA expression in fibroblasts, measured by quantitative real-time polymerase chain reaction (qPCR) and standardized against GAPDH. The graph shows the normalized relative DNAJC12 mRNA levels in two affected individuals (B-IV-1 and B-IV-2) and three unaffected age-matched healthy control individuals. (B and C) Representative western blot (B) and densitometric quantification (C, left) of the DNAJC12 protein levels in fibroblasts from three unaffected age-matched healthy control individuals (C1–C3), in fibroblasts from the heterozygous unaffected father of B-IV-1 and B-IV-2 (Het), and in fibroblasts with the homozygous missense variant (c.215G>C, C-II-4), the homozygous del6943 (A-IV-2), and the homozygous canonical splice variant (c.158−2A>T, B-IV-1 and B-IV-2). Densitometric analysis of DNAJC12 protein (C, right) was performed in fibroblasts from individual C-II-4 (n = 3) and in fibroblasts from three unaffected age-matched healthy control individuals (n = 3). DNAJC12 level was normalized to β-actin. Results are presented as means ± SEM; ∗p < 0.05. The American Journal of Human Genetics 2017 100, 257-266DOI: (10.1016/j.ajhg.2017.01.002) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Overview of the DNAJC12, PAH, TH, and TPH2 Protein Interaction Network, as Determined by Immunoprecipitation-Mass Spectrometry Analysis C-terminally tagged DNAJC12, PAH, TH, and TPH2 were immunopurified from HEK293 cells, and protein complexes were analyzed by liquid chromatography-mass spectrometry. CompPASS analysis was performed in technical duplicates. Proteins with NWD scores > 1, ASPM > 2, and entropy values > 0.7 that were reproducibly detected in the two CompPASS analyses were considered high-confidence interactors. Baits are represented in red. High-confidence interacting proteins (HCIPs) are represented in gray. The American Journal of Human Genetics 2017 100, 257-266DOI: (10.1016/j.ajhg.2017.01.002) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Phenylalanine Hydroxylase Enzyme Activity Is Reduced in the Presence of DNAJC12 Mutations (A) PAH activity was measured using liquid chromatography-electrospray ionization tandem mass spectrometry in fibroblasts with the homozygous missense variant (c.215G>C, individual C-II-4) and in fibroblasts from an unaffected age-matched healthy control after 5 μg or 10 μg PAH plasmids transfection. (B) Western blot assay of PAH, DNAJC12, and β-actin proteins in individual C-II-4 and control fibroblasts after 5 μg or 10 μg PAH plasmids transfection. The American Journal of Human Genetics 2017 100, 257-266DOI: (10.1016/j.ajhg.2017.01.002) Copyright © 2017 American Society of Human Genetics Terms and Conditions