title: Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.
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.
authors.affiliation: 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: matthis.synofzik@uni-tuebingen.de.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: 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.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Kopajtich
authors.affiliation: 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.
authors.forename: Matteo
authors.initials: M
authors.lastname: Gorza
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Doron
authors.initials: D
authors.lastname: Rapaport
authors.affiliation: Medical Biochemistry and Molecular Biology, University of Saarland, 66421 Homburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Greiner
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schönfeld
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Georg August University, 37075 Göttingen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Freiberg
authors.affiliation: Medical Biochemistry and Molecular Biology, University of Saarland, 66421 Homburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schorr
authors.affiliation: Institute for Epidemiology and Medical Biometry, University of Ulm, 89081 Ulm, Germany.
authors.forename: Reinhard W
authors.initials: RW
authors.lastname: Holl
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: Institute of Pathology and Neuropathology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Fallier-Becker
authors.affiliation: Medical Biochemistry and Molecular Biology, University of Saarland, 66421 Homburg, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: 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.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: 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: ludger.schoels@uni-tuebingen.de.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
mesh_terms: D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000000981:diagnostic imaging / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D019578:Multiple System Atrophy / Q000000981:diagnostic imaging / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C494651:DNAJC3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins