Journal Article

DZNE-2020-04013

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.

Synofzik, M. (First author)DZNE* ; Haack, T. B. ; Kopajtich, R. ; Gorza, M. ; Rapaport, D. ; Greiner, M. ; Schoenfeld, C.DZNE* ; Freiberg, C. ; Schorr, S. ; Holl, R. W. ; Gonzalez, M. A. ; Fritsche, A. ; Fallier-Becker, P. ; Zimmermann, R. ; Strom, T. M. ; Meitinger, T. ; Züchner, S. ; Schüle, R.DZNE* ; Schöls, L.DZNE* ; Prokisch, H.

2014
Elsevier New York, NY

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Please use a persistent id in citations: 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.

Keyword(s): Endoplasmic Reticulum Chaperone BiP (MeSH) ; Adolescent (MeSH) ; Adult (MeSH) ; Ataxia: genetics (MeSH) ; Diabetes Mellitus, Type 1: diagnostic imaging (MeSH) ; Diabetes Mellitus, Type 1: genetics (MeSH) ; Exome: genetics (MeSH) ; Female (MeSH) ; Fibroblasts (MeSH) ; Gene Expression Regulation (MeSH) ; HSP40 Heat-Shock Proteins: genetics (MeSH) ; HSP40 Heat-Shock Proteins: metabolism (MeSH) ; Heat-Shock Proteins: genetics (MeSH) ; Homozygote (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Models, Molecular (MeSH) ; Multiple System Atrophy: diagnostic imaging (MeSH) ; Multiple System Atrophy: genetics (MeSH) ; Mutation (MeSH) ; Pedigree (MeSH) ; Phenotype (MeSH) ; Radiography (MeSH) ; Sequence Analysis, DNA (MeSH) ; Young Adult (MeSH) ; DNAJC3 protein, human ; HSP40 Heat-Shock Proteins ; Heat-Shock Proteins ; molecular chaperone GRP78

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Tübingen common (Tübingen common)
3. Functional Neurogeriatrics (AG Maetzler)
4. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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