Absence of an Orphan Mitochondrial Protein, C19orf12, Causes a Distinct Clinical Subtype of Neurodegeneration with Brain Iron Accumulation Monika B.

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Absence of an Orphan Mitochondrial Protein, C19orf12, Causes a Distinct Clinical Subtype of Neurodegeneration with Brain Iron Accumulation Monika B. Hartig, Arcangela Iuso, Tobias Haack, Tomasz Kmiec, Elzbieta Jurkiewicz, Katharina Heim, Sigrun Roeber, Victoria Tarabin, Sabrina Dusi, Malgorzata Krajewska-Walasek, Sergiusz Jozwiak, Maja Hempel, Juliane Winkelmann, Matthias Elstner, Konrad Oexle, Thomas Klopstock, Wolfgang Mueller-Felber, Thomas Gasser, Claudia Trenkwalder, Valeria Tiranti, Hans Kretzschmar, Gerd Schmitz, Tim M. Strom, Thomas Meitinger, Holger Prokisch The American Journal of Human Genetics Volume 89, Issue 4, Pages 543-550 (October 2011) DOI: 10.1016/j.ajhg.2011.09.007 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of the NBIA Family Used for Homozygosity Mapping Mutated and nonmutated alleles are indicated. The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Gene Structure and Identified Disease Alleles Gene structure of the two isoforms of C19orf12 with the identified mutations. The predicted transmembrane domain is marked in yellow. Mutation nomenclature of the C19orf12 gene is based on splice variant 1 (NM_001031726.2). RefSeq accession number of splice variant 2 is NM_031448.3. The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Evolutionary Conservation of C19orf12 Multiple sequences of C19orf12 orthologs were aligned with CLUSTALW2. Amino acids are indicated as identical (red), highly similar (green), and similar (blue). The predicted transmembrane domain is marked in yellow. The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Magnetic Resonance Images of Cases with the Homozygous C19orf12 Deletion c.204_214del11, p.Gly69ArgfsX10 Axial T2-weighted magnetic resonance imaging (1.5 T) shows a bilateral hypointensity of the globus pallidus (A) and substantia nigra (B). The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 5 Brain Histopathology of an Individual with the Homozygous C19orf12 Missense Mutation c.205G>A, p.Gly69Arg, p.Gly69Arg (A) Hematoxylin and eosin staining and (B) Prussian blue staining of the globus pallidus showed iron-containing deposits in neurons (insert in B) that are more diffusely distributed in astrocytes and very dense in perivascular macrophages (arrowhead in A) as well as many axonal spheroids (arrows in A) that were stained faintly by antibodies against APP (insert in B). Spheroids were found in the globus pallidus, putamen, and caudate nucleus, and at a lower density in the thalamus, internal capsule, brainstem, cerebral cortex, dentate nucleus, and spinal cord. Numerous α-synuclein-positive Lewy bodies, Lewy body-like inclusions, and some Lewy neurites were detected in the frontal cortex (C) and other neocortical areas; the hippocampus was less severely affected. Similar histopathology with Lewy bodies and Lewy body-like inclusions was found in the brain stem, including the substantia nigra, basal ganglia, cortex, and spinal cord (not shown). Some seemingly extracellular α-synuclein-positive deposits were noted in various areas (D, showing the external capsule and claustrum). Hyperphosphorylated tau-containing neuronal inclusions were identified in the hippocampus (E). The tau protein often seemed densely packed around pyramidal cell nuclei as is sometimes observed in tauopathies (F). Only a very small number of tau-positive inclusions stained with silver staining methods (Bodian, Bielschowsky, Gallyas) but did not show fibrils. Tufted astrocytes or coiled bodies were not seen. No neurofibrillary tangels (NFT) were seen in the globus pallidus or the substantia nigra. However, tau-positive extracellular punctuate and globular or irregularly shaped structures were found widely distributed in the hippocampus and the neocortex. In some instances these structures seemed to be associated with astrocytes. The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 6 Subcellular Localization of C19orf12 A C19orf12-GFP fusion protein (upper α-synuclein-positive deposits were noted in various areas [E]) and C19orf12 untagged protein (lower panel) exhibit a mitochondrial localization in transiently transfected and in stably transduced fibroblasts, respectively. Mitochondria were stained with mitochondrial single strand binding protein (anti-mtSSBP; red) or anti-porin (green). Nuclear DNA was stained with DAPI (blue). The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 7 Subcellular Localization of C19orf12 in Mitochondria NDHF-neo cells were harvested to obtain mitochondria, ER, and cytosol fractions. Equal amount of proteins (20 μg) from each fraction were resolved by SDS-PAGE and immunoblotted for C19orf12 with an antibody against the whole protein. Porin and calnexin were used as a loading control of inner mitochondrial membrane proteins and endoplasmatic reticulum, respectively. The American Journal of Human Genetics 2011 89, 543-550DOI: (10.1016/j.ajhg.2011.09.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions