Matthis Synofzik, Tobias B

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Absence of BiP Co-chaperone DNAJC3 Causes Diabetes Mellitus and Multisystemic Neurodegeneration Matthis Synofzik, Tobias B. Haack, Robert Kopajtich, Matteo Gorza, Doron Rapaport, Markus Greiner, Caroline Schönfeld, Clemens Freiberg, Stefan Schorr, Reinhard W. Holl, Michael A. Gonzalez, Andreas Fritsche, Petra Fallier-Becker, Richard Zimmermann, Tim M. Strom, Thomas Meitinger, Stephan Züchner, Rebecca Schüle, Ludger Schöls, Holger Prokisch The American Journal of Human Genetics Volume 95, Issue 6, Pages 689-697 (December 2014) DOI: 10.1016/j.ajhg.2014.10.013 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and DNJAC3 Mutations of the Index Families (A) Pedigrees of the index families and segregation of the mutations identified in DNAJC3. Family 1 includes one unaffected and three affected children of unrelated parents, and family 2 has two affected children of first-degree consanguineous parents. The identified DNAJC3 variants segregated with the disease in all affected members of the two families, and testing of parents demonstrated that their respective mutations are located in trans. Abbreviations are as follows: mut, mutation; and +, wild-type. (B) Representation of identified DNAJC3 mutations. A schematic of the exon-intron arrangement of DNAJC3 (RefSeq NM_ 006260.4) includes the positions of the stop mutation identified in family 1 (top) and the deletion identified in family 2 (bottom). The electropherogram of the deletion breakpoint was analyzed with primers F1 and R1. Coding regions are indicated as blue boxes. The American Journal of Human Genetics 2014 95, 689-697DOI: (10.1016/j.ajhg.2014.10.013) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Immunoblot of DNAJC3 The immunoblot shows the absence of DNAJC3 in all affected subjects (with blue IDs) of both families, whereas the two heterozygous parents (with black IDs) of the siblings in family 2 showed normal protein levels. Immunoblot analysis was performed as described previously.11 DNAJC3 antibody (rabbit, Cell Signaling Technology) was used at 1:1,000. β-actin antibody (Sigma-Aldrich) was used at 1:10,000. The American Journal of Human Genetics 2014 95, 689-697DOI: (10.1016/j.ajhg.2014.10.013) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 MRI and Body Stature of Subjects with DNAJC3 Loss-of-Function Mutations MRI of subjects with DNAJC3 loss-of-function mutations (A–G) and short stature and low BMI in an exemplary affected subject (H). MRI of index subjects II.2 (61691) from family 1 (A–D) and II.1 (66050) from family 2 (E–G) revealed generalized supra- and infratentorial atrophy pronounced in the cervical and thoracic cord (arrowheads; A, D, and E), cerebellar vermis (arrows; A and E), and crus cerebri and midbrain (arrows; C and F) in both subjects and in the pre- and postcentral gyrus in subject II.2 from family 1 (arrows; B). Subject II.1 (66050) from family 2 also showed several small T2 hyperintense lesions without contrast enhancement bilaterally in the frontoparietal and periventricular regions (arrows; G). In index family 1, affected subject II.3 (61693; H, right) has a lower BMI and shorter stature than her unaffected sister, II.1 (54829; H, left). The American Journal of Human Genetics 2014 95, 689-697DOI: (10.1016/j.ajhg.2014.10.013) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 Role of DNAJC3 in the UPR and Its Interaction with Other Proteins Associated with Human Disease DNAJC3 (brown ovals) belongs to the DNAJ proteins localized in the lumen of the ER. It directly binds and recruits unfolded proteins (twisted black lines) in order to hand them over to the molecular chaperone BiP (green boxes). BiP is a central target of UPR signaling. Inter alia, it interacts with SIL1 (red circles), a nucleotide exchange factor, to restore adequate folding of misfolded proteins. An overwhelming load of misfolded proteins requires more of the available BiP to bind to the exposed hydrophobic regions of these misfolded proteins. To meet this requirement, BiP dissociates from ER-transmembrane sensors, such as PERK (blue circles). The oligomerization of PERK and the consequent autophosphorylation of the free luminal domain lead to the activation of PERK. The activated cytosolic domain of PERK causes translational attenuation by directly phosphorylating the α subunit of the regulating initiator of the mRNA translation machinery, eIF-2α (blue boxes). This attenuation of translation further reduces the stress induced by misfolded proteins. Several mutations in genes encoding proteins of these UPR pathways are well established in human diseases. Mutations in EIFKA3, encoding PERK, cause WRS, which is characterized by young-onset nonautoimmune insulin-requiring diabetes, skeletal dysplasia, and short stature and thereby resembles several hallmarks of the DNAJC3-deficiency phenotype. Defects in SIL1 cause MSS.18,19 Clinical manifestations of MSS include early-onset cerebellar ataxia and short stature, thus also mirroring hallmarks of DNAJC3 disease. The American Journal of Human Genetics 2014 95, 689-697DOI: (10.1016/j.ajhg.2014.10.013) Copyright © 2014 The American Society of Human Genetics Terms and Conditions