Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6 Ilham Ratbi, Kim D. Falkenberg, Manou Sommen, Nada.

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Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6 Ilham Ratbi, Kim D. Falkenberg, Manou Sommen, Nada Al-Sheqaih, Soukaina Guaoua, Geert Vandeweyer, Jill E. Urquhart, Kate E. Chandler, Simon G. Williams, Neil A. Roberts, Mustapha El Alloussi, Graeme C. Black, Sacha Ferdinandusse, Hind Ramdi, Audrey Heimler, Alan Fryer, Sally-Ann Lynch, Nicola Cooper, Kai Ren Ong, Claire E.L. Smith, Christopher F. Inglehearn, Alan J. Mighell, Claire Elcock, James A. Poulter, Marc Tischkowitz, Sally J. Davies, Abdelaziz Sefiani, Aleksandr A. Mironov, William G. Newman, Hans R. Waterham, Guy Van Camp The American Journal of Human Genetics Volume 97, Issue 4, Pages 535-545 (October 2015) DOI: 10.1016/j.ajhg.2015.08.011 Copyright © 2015 The Authors Terms and Conditions

Figure 1 Pedigrees of the Families Affected by HS, Illustration of Clinical Characteristics of Individual F5-II:2, and Air-Conduction Audiograms of HS Individuals (A) Affected individuals are shaded. Arrows indicate individuals in whom WES was performed and blood and/or fibroblasts were analyzed. For family 1, additional exomes were sequenced for members I:1, II:1, and II:3. DNA for cosegregation analysis was available from family members with an asterisk. (B) An orthopantogram of individual F5-II:2 shows severe amelogenesis imperfecta. (C) A retinal photograph taken when individual F5-II:2 was 20 years old shows marked mottling of the retinal pigment epithelium. (D) A fingernail of individual F5-II:2 shows evidence of onychoschizia and Beau’s lines. (E) An air-conduction audiogram of individual F5-II:2. (F) An air-conduction audiogram of individual F5-II:3. The American Journal of Human Genetics 2015 97, 535-545DOI: (10.1016/j.ajhg.2015.08.011) Copyright © 2015 The Authors Terms and Conditions

Figure 2 Location of HS-Associated Variants in PEX1 and PEX6 Arrows mark the amino acid positions of the identified alterations. The corresponding position of the alteration at the cDNA level is given between parentheses; the superscript number indicates the family in which the alteration was identified. Gray areas mark the functional AAA domains of the proteins (including the highly conserved Walker motifs in dark gray). The American Journal of Human Genetics 2015 97, 535-545DOI: (10.1016/j.ajhg.2015.08.011) Copyright © 2015 The Authors Terms and Conditions

Figure 3 Peroxisomal Phenotype of Cells from Individuals with HS Skin fibroblasts of individuals F1-III:3 and F5-II:2 and control fibroblasts were cultured at 37°C or 40°C and immunolabeled for PMP70 (ABCD3) (red, peroxisomal membrane protein) and catalase (green, peroxisomal matrix protein). In cells of individuals with HS, the staining at 37°C revealed a mosaic pattern showing cells with a normal peroxisomal phenotype (positive for both PMP70 and catalase) and cells with import-incompetent peroxisomes (“ghosts;” positive for PMP70 and negative for catalase). At 40°C, the vast majority of these cells showed import-incompetent peroxisomes (positive for PMP70 and negative for catalase). Control cells showed a normal peroxisomal phenotype in all conditions. The American Journal of Human Genetics 2015 97, 535-545DOI: (10.1016/j.ajhg.2015.08.011) Copyright © 2015 The Authors Terms and Conditions

Figure 4 Effect of the PEX1 and PEX6 Mutations on Peroxisome Biogenesis Fibroblasts deficient in PEX1 or PEX6 were transfected with a peroxisomal fluorescent marker and expression plasmids containing the constructed PEX variants. The ratio of complemented cells was quantified per construct and normalized to the maximal complementation capability as measured in co-transfections of peroxisomal markers with the functional PEX versions (positive controls set as 100%). n = 5–7 per construct (mean ± SEM); ∗p < 0.05 (statistical analysis by one-sample Wilcoxon signed-rank test for which the null hypothesis, H0, was that the median sample value equals the maximal complementation capability [100%], which is the ratio of peroxisome-positive cells to wild-type PEX-complemented cells). The American Journal of Human Genetics 2015 97, 535-545DOI: (10.1016/j.ajhg.2015.08.011) Copyright © 2015 The Authors Terms and Conditions