TY  - JOUR
AU  - Synofzik, Matthis
AU  - Haack, Tobias B
AU  - Kopajtich, Robert
AU  - Gorza, Matteo
AU  - Rapaport, Doron
AU  - Greiner, Markus
AU  - Schoenfeld, Caroline
AU  - Freiberg, Clemens
AU  - Schorr, Stefan
AU  - Holl, Reinhard W
AU  - Gonzalez, Michael A
AU  - Fritsche, Andreas
AU  - Fallier-Becker, Petra
AU  - Zimmermann, Richard
AU  - Strom, Tim M
AU  - Meitinger, Thomas
AU  - Züchner, Stephan
AU  - Schüle, Rebecca
AU  - Schöls, Ludger
AU  - Prokisch, Holger
TI  - Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.
JO  - The American journal of human genetics
VL  - 95
IS  - 6
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2020-04013
SP  - 689-697
PY  - 2014
AB  - 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.
KW  - Endoplasmic Reticulum Chaperone BiP
KW  - Adolescent
KW  - Adult
KW  - Ataxia: genetics
KW  - Diabetes Mellitus, Type 1: diagnostic imaging
KW  - Diabetes Mellitus, Type 1: genetics
KW  - Exome: genetics
KW  - Female
KW  - Fibroblasts
KW  - Gene Expression Regulation
KW  - HSP40 Heat-Shock Proteins: genetics
KW  - HSP40 Heat-Shock Proteins: metabolism
KW  - Heat-Shock Proteins: genetics
KW  - Homozygote
KW  - Humans
KW  - Male
KW  - Models, Molecular
KW  - Multiple System Atrophy: diagnostic imaging
KW  - Multiple System Atrophy: genetics
KW  - Mutation
KW  - Pedigree
KW  - Phenotype
KW  - Radiography
KW  - Sequence Analysis, DNA
KW  - Young Adult
KW  - DNAJC3 protein, human (NLM Chemicals)
KW  - HSP40 Heat-Shock Proteins (NLM Chemicals)
KW  - Heat-Shock Proteins (NLM Chemicals)
KW  - molecular chaperone GRP78 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25466870
C2  - pmc:PMC4259973
DO  - DOI:10.1016/j.ajhg.2014.10.013
UR  - https://pub.dzne.de/record/137691
ER  -