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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 689-697 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 95 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 4 2014 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Absence of BiP Co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. / Synofzik, Matthis; Haack, Tobias B.; Kopajtich, Robert; Gorza, Matteo; Rapaport, Doron; Greiner, Markus; Schönfeld, Caroline; Freiberg, Clemens; Schorr, Stefan; Holl, Reinhard W.; Gonzalez, Michael A.; Fritsche, Andreas; Fallier-Becker, Petra; Zimmermann, Richard; Strom, Tim M.; Meitinger, Thomas; Zuchner, Stephan L; Schüle, Rebecca; Schöls, Ludger; Prokisch, Holger.
In: American Journal of Human Genetics, Vol. 95, No. 6, 04.12.2014, p. 689-697.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Absence of BiP Co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration
AU - Synofzik, Matthis
AU - Haack, Tobias B.
AU - Kopajtich, Robert
AU - Gorza, Matteo
AU - Rapaport, Doron
AU - Greiner, Markus
AU - Schönfeld, 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 - Zuchner, Stephan L
AU - Schüle, Rebecca
AU - Schöls, Ludger
AU - Prokisch, Holger
PY - 2014/12/4
Y1 - 2014/12/4
N2 - 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.
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.
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U2 - 10.1016/j.ajhg.2014.10.013
DO - 10.1016/j.ajhg.2014.10.013
M3 - Article
C2 - 25466870
AN - SCOPUS:84919701047
VL - 95
SP - 689
EP - 697
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -