Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration

Am J Hum Genet. 2014 Dec 4;95(6):689-97. doi: 10.1016/j.ajhg.2014.10.013.

Matthis Synofzik ¹, Tobias B Haack ², Robert Kopajtich ², Matteo Gorza ², Doron Rapaport ³, Markus Greiner ⁴, Caroline Schönfeld ⁵, Clemens Freiberg ⁶, Stefan Schorr ⁴, Reinhard W Holl ⁷, Michael A Gonzalez ⁸, Andreas Fritsche ⁹, Petra Fallier-Becker ¹⁰, Richard Zimmermann ⁴, Tim M Strom ², Thomas Meitinger ², Stephan Züchner ⁸, Rebecca Schüle ¹¹, Ludger Schöls ¹², Holger Prokisch ²

Affiliations

1 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, 72076 Tübingen, Germany. Electronic address: [email protected].
2 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
3 Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
4 Medical Biochemistry and Molecular Biology, University of Saarland, 66421 Homburg, Germany.
5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, 72076 Tübingen, Germany; Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
6 Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Georg August University, 37075 Göttingen, Germany.
7 Institute for Epidemiology and Medical Biometry, University of Ulm, 89081 Ulm, Germany.
8 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
9 Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, 72076 Tübingen, Germany.
10 Institute of Pathology and Neuropathology, University of Tübingen, 72076 Tübingen, Germany.
11 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, 72076 Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
12 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, 72076 Tübingen, Germany. Electronic address: [email protected].

PMID: 25466870 DOI: 10.1016/j.ajhg.2014.10.013

Abstract

Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. Here, we show that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. Exome sequencing identified a homozygous stop mutation in DNAJC3. Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion. DNAJC3 was absent in fibroblasts from all affected subjects in both families. To delineate the phenotypic and mutational spectrum and the genetic variability of DNAJC3, we analyzed 8,603 exomes, including 506 from families affected by diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, or hearing loss. This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype. Our findings demonstrate that loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans. Moreover, they present a common denominator for diabetes and widespread neurodegeneration. This complements findings from mice in which knockout of Dnajc3 leads to diabetes and modifies disease in a neurodegenerative model of Marinesco-Sjögren syndrome.

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