Cole-Carpenter Syndrome Is Caused by a Heterozygous Missense Mutation in P4HB Frank Rauch, Somayyeh Fahiminiya, Jacek Majewski, Jian Carrot-Zhang, Sergei.

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Cole-Carpenter Syndrome Is Caused by a Heterozygous Missense Mutation in P4HB Frank Rauch, Somayyeh Fahiminiya, Jacek Majewski, Jian Carrot-Zhang, Sergei Boudko, Francis Glorieux, John S. Mort, Hans-Peter Bächinger, Pierre Moffatt The American Journal of Human Genetics Volume 96, Issue 3, Pages 425-431 (March 2015) DOI: 10.1016/j.ajhg.2014.12.027 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Radiographic Findings in Individual 2 at 18 Years of Age (A) Lateral skull radiograph showing severe midface hypoplasia. (B) The right upper extremity is severely deformed. (C) In the lower extremities, both femurs and tibias have undergone intramedullary rodding surgery. Epiphyses of both distal femurs are wide and seem filled with nodular structures (“popcorn epiphyses”). The right femur shows a large cystic area (asterisk) and no bone is visible in the midshaft area (arrow). (D) Wide epiphyses of the metacarpal and digital bones, thin cortices and a cystic appearance. Some of the end phalanges seem to be partially resorbed (arrows). The American Journal of Human Genetics 2015 96, 425-431DOI: (10.1016/j.ajhg.2014.12.027) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Confirmation of the Heterozygous P4HB Mutation in Individuals 1 and 2, and Prediction of Its Impact on PDI (A) Pedigrees of the families of individual 1 (II-1 in family 1) and individual 2 (II-1 in family 2) and Sanger sequencing chromatogram at the site of c.1178A in P4HB (indicated by arrows). Individuals 1 and 2 are heterozygous for the c.1178A>C variant. The chromatograms of the father of individual 1 indicate the presence of the c.1178A>C variant with a lower relative peak size in DNA extracted from saliva, but not in DNA extracted from skin fibroblasts. (B) Amino acid conservation of the Tyr393 residue in PDI (NP_000909.2). Tyr393 and the following 8 residues are perfectly conserved among species. Tyrosine at the corresponding position is also conserved among the various PDI family members. (C) Schematic representation of PDI and of the coding exons of P4HB cDNA (NM_000918.3). The locations of the exons are aligned relative to the regions of PDI that each exon encodes. The position of the mutation reported in the present study is indicated. The domains of PDI are represented by a, b, b′, a′. An endoplasmic reticulum retention motif (KDEL) is present at the C terminus. (D) Model of the critical region in PDI. Cys397 and Cys400 are the active site residues, which normally form a reversible disulfide bond. When Tyr393 is mutated to Cys393, the new Cys393 is sterically close to Cys400 and thus might interfere with the active site of PDI. The American Journal of Human Genetics 2015 96, 425-431DOI: (10.1016/j.ajhg.2014.12.027) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Effect of the p.Tyr393Cys Variant on the Disulfide Isomerase Activity of PDI Scrambled RNase A (Scr-RNase) was incubated for 5 min with 1.0 μM of either wild-type PDI (PDI-wt) or PDI carrying the p.Tyr393Cys variant (PDI-Cys393). RNase activity (final RNase A concentration: 4 μM) was determined by adding cytidine 2′,3′-cyclic monophosphate (cCMP, Sigma-Aldrich) (final concentration: 2 mM). The hydrolysis of cCMP by active RNase A was monitored by measuring the absorbance at 296 nm. Changes in absorbance (means and SE of four independent experiments) are shown every 5 min. The American Journal of Human Genetics 2015 96, 425-431DOI: (10.1016/j.ajhg.2014.12.027) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Protein Analyses in Skin Fibroblasts (A) Western blot of PDI under reducing and non-reducing conditions. The amount of PDI is similar in a control (C), individual 1 (P1), and the father of individual 1 (I-1), regardless of whether ascorbate is added or not. Under non-reducing conditions (without addition of dithiothreitol, to preserve disulfide bonds), additional bands are visible in individual 1, indicating that PDI with the p.Tyr393Cys variant forms stable disulfide bridges with other proteins. (B) Immunofluorescence. PDI and type I procollagen have a more vesicular pattern in skin fibroblasts from individual 2 (P2) as compared to the control. (C) Western blot for HSP47. Accumulation of heat shock protein 47 (HSP47) is increased in fibroblasts from individual 1 (P1) and 2 (P2), suggesting endoplasmic reticulum stress. Ascorbate was added to the culture to stimulate collagen type I secretion. This did not have a discernible effect on HSP47 accumulation. The American Journal of Human Genetics 2015 96, 425-431DOI: (10.1016/j.ajhg.2014.12.027) Copyright © 2015 The American Society of Human Genetics Terms and Conditions