Gloria Brea-Calvo, Tobias B

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COQ4 Mutations Cause a Broad Spectrum of Mitochondrial Disorders Associated with CoQ10 Deficiency Gloria Brea-Calvo, Tobias B. Haack, Daniela Karall, Akira Ohtake, Federica Invernizzi, Rosalba Carrozzo, Laura Kremer, Sabrina Dusi, Christine Fauth, Sabine Scholl-Bürgi, Elisabeth Graf, Uwe Ahting, Nicoletta Resta, Nicola Laforgia, Daniela Verrigni, Yasushi Okazaki, Masakazu Kohda, Diego Martinelli, Peter Freisinger, Tim M. Strom, Thomas Meitinger, Costanza Lamperti, Atilano Lacson, Placido Navas, Johannes A. Mayr, Enrico Bertini, Kei Murayama, Massimo Zeviani, Holger Prokisch, Daniele Ghezzi The American Journal of Human Genetics Volume 96, Issue 2, Pages 309-317 (February 2015) DOI: 10.1016/j.ajhg.2014.12.023 Copyright © 2015 The Authors Terms and Conditions

Figure 1 Pedigrees of Investigated Families and COQ4 Structure and Conservation of Identified Mutations (A) Pedigrees of four families affected by mutations in COQ4. The mutation status of affected and unaffected family members is indicated by closed and open symbols, respectively. (B) COQ4 structure showing the identified mutations. The structure of the gene product, COQ4, is also shown with known domains and localization and conservation of amino acid residues affected by the mutations. Intronic regions are not drawn to scale. The American Journal of Human Genetics 2015 96, 309-317DOI: (10.1016/j.ajhg.2014.12.023) Copyright © 2015 The Authors Terms and Conditions

Figure 2 Biochemical Studies in COQ4 Mutant Muscle and Fibroblasts (A) CoQ10 in muscle from affected subjects S1 and S3–S5 is reported as a percentage of the mean of control values (the analyses were performed in different laboratories, and the reference values are diverse; see text). Data are reported after normalization to protein content or CS activity. (B) Maximal respiration rate (MRR) measured in fibroblasts from subjects S1, S4, and S5; MRR values are expressed as percentages of MRR values obtained in control fibroblasts. The graphs represent the mean values from two independent experiments, each with six to eight replicates. Error bars represent the SD. (C) Immunoblot analysis of COQ4 in fibroblasts from subjects S1, S4, and S5 and control individuals (Ct). Arrowheads indicate the band corresponding to COQ4. An antibody against tubulin was used as a loading control. The American Journal of Human Genetics 2015 96, 309-317DOI: (10.1016/j.ajhg.2014.12.023) Copyright © 2015 The Authors Terms and Conditions

Figure 3 Yeast Studies (A) Glycerol (YPG) growth of transformed ΔCOQ4 yeast with the different mutated versions of human COQ4 (pYES2.1, empty vector; hCOQ4, pYES:hCOQ4WT; yCOQ4, pYES:yCOQ4WT; c.433C>G, pYES:hcoq4p.Arg145Gly; c.421C>T, pYES:hcoq4p.Arg141∗; c.718C>T, pYES:hcoq4p.Arg240Cys; c.155T>C, pYES:hcoq4p.Leu52Ser; c.521_523delCCA, pYES:hcoq4p.Thr174del; c.190C>T, pYES:hcoq4p.Pro64Ser; c.155T>C and c.521_523delCCA, pYES:hcoq4p.Leu52Ser/p.Thr174del; and c.421C>T and c.718C>T, pYES:hcoq4p.Arg141∗/p.Arg240Cys). WT indicates the wild-type yeast transformed with the YES2.1 empty vector. Cells were grown in selective medium for 16 hr, induced in galactose for 4 hr, and inoculated in YPG at 0.1 U of optical density (OD) at 600 nm. Growth at 30°C was monitored over 5 days by measurement of OD cultures at 600 nm. (B) Yeast mitochondrial CoQ6 levels. Purified mitochondria lipid extraction and high-performance-liquid-chromatography quantification of CoQ6 was performed in the ΔCOQ4 strain transformed with the empty vector (pYES2.1), WT yeast (yCOQ4), or human (hCOQ4) or hcoq4p.Arg145Gly (c.433C>G) COQ4 genes. A WT strain transformed with the empty vector was included as a positive control. Error bars represent the SD. The American Journal of Human Genetics 2015 96, 309-317DOI: (10.1016/j.ajhg.2014.12.023) Copyright © 2015 The Authors Terms and Conditions