title: A splicing mutation in the novel mitochondrial protein DNAJC11 causes motor neuron pathology associated with cristae disorganization, and lymphoid abnormalities in mice.
abstract: Mitochondrial structure and function is emerging as a major contributor to neuromuscular disease, highlighting the need for the complete elucidation of the underlying molecular and pathophysiological mechanisms. Following a forward genetics approach with N-ethyl-N-nitrosourea (ENU)-mediated random mutagenesis, we identified a novel mouse model of autosomal recessive neuromuscular disease caused by a splice-site hypomorphic mutation in a novel gene of unknown function, DnaJC11. Recent findings have demonstrated that DNAJC11 protein co-immunoprecipitates with proteins of the mitochondrial contact site (MICOS) complex involved in the formation of mitochondrial cristae and cristae junctions. Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. The causal role of the identified mutation in DnaJC11 was verified in rescue experiments by overexpressing the human ortholog. The full length 63 kDa isoform of human DNAJC11 was shown to localize in the periphery of the mitochondrial outer membrane whereas putative additional isoforms displayed differential submitochondrial localization. Moreover, we showed that DNAJC11 is assembled in a high molecular weight complex, similarly to mitofilin and that downregulation of mitofilin or SAM50 affected the levels of DNAJC11 in HeLa cells. Our findings provide the first mouse mutant for a putative MICOS protein and establish a link between DNAJC11 and neuromuscular diseases.
authors.affiliation: Department of Biotechnology, Agricultural University of Athens, Athens, Greece; Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Fotis
authors.initials: F
authors.lastname: Ioakeimidis
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Ott
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Kozjak-Pavlovic
authors.affiliation: Department of Biotechnology, Agricultural University of Athens, Athens, Greece; Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Foteini
authors.initials: F
authors.lastname: Violitzi
authors.affiliation: Department of Biotechnology, Agricultural University of Athens, Athens, Greece; Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Vagelis
authors.initials: V
authors.lastname: Rinotas
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Makrinou
authors.affiliation: Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Elias
authors.initials: E
authors.lastname: Eliopoulos
authors.affiliation: Department of Crop Science, Agricultural University of Athens, Athens, Greece.
authors.forename: Costas
authors.initials: C
authors.lastname: Fasseas
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.affiliation: Department of Biotechnology, Agricultural University of Athens, Athens, Greece; Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Douni
mesh_terms: D000818:Animals; D001483:Base Sequence; D057809:HEK293 Cells; D006801:Humans; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D051379:Mice; D051336:Mitochondrial Membranes / Q000473:pathology*; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D010641:Phenotype; D021381:Protein Transport; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology
chemical_list: C487553:DNAJC11 protein, human; D011506:Proteins
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