Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism

Abstract

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data. Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data. Since its initial association with a neurological disorder,1Harel T. Yoon W.H. Garone C. Gu S. Coban-Akdemir Z. Eldomery M.K. Posey J.E. Jhangiani S.N. Rosenfeld J.A. Cho M.T. et al.Baylor-Hopkins Center for Mendelian GenomicsUniversity of Washington Center for Mendelian GenomicsRecurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.Am. J. Hum. Genet. 2016; 99: 831-845Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar it has become apparent that disruption of the ATAD3 cluster, and more specifically ATAD3A (MIM: 612316), is a significant cause of pediatric disease. Variants at this locus are associated with a wide phenotypic spectrum, including pontocerebellar hypoplasia,2Desai R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar hereditary spastic paraplegia,3Cooper H.M. Yang Y. Ylikallio E. Khairullin R. Woldegebriel R. Lin K.-L. Euro L. Palin E. Wolf A. Trokovic R. et al.ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.Hum. Mol. Genet. 2017; 26: 1432-1443Crossref PubMed Scopus (33) Google Scholar and a syndromic neurological disorder characterized by peripheral neuropathy, hypotonia, cardiomyopathy, optic atrophy, cerebellar atrophy, and seizures:1Harel T. Yoon W.H. Garone C. Gu S. Coban-Akdemir Z. Eldomery M.K. Posey J.E. Jhangiani S.N. Rosenfeld J.A. Cho M.T. et al.Baylor-Hopkins Center for Mendelian GenomicsUniversity of Washington Center for Mendelian GenomicsRecurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.Am. J. Hum. Genet. 2016; 99: 831-845Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Harel-Yoon syndrome (HAYOS [MIM: 617183]). The different phenotypes can be attributed to a spectrum of disease-causing variants that includes bi-allelic hypomorphic variants, bi-allelic deletions, and monoallelic dominant-negative missense variants. Here, we report two de novo intergenic duplications in the ATAD3 cluster identified in five unrelated neonates with shared phenotypes including corneal clouding, cardiomyopathy, hypotonia, and white matter changes, thus expanding the genotype spectrum of ATAD3-related disorders. The ATAD3 cluster is composed of three paralogs with extensive sequence homology, formed through tandem segmental duplication: ATAD3A, ATAD3B (MIM: 612317), and ATAD3C (MIM: 617227). ATAD3A and ATAD3B are protein-coding genes of near identical sequence, differing primarily due to a stop-loss mutation in ATAD3B that extends the protein by 62 amino acids; ATAD3C is not known to be expressed. ATAD3A is a transmembrane ATPase, which is predicted to form hexamers,4Baudier J. ATAD3 proteins: brokers of a mitochondria-endoplasmic reticulum connection in mammalian cells.Biol. Rev. Camb. Philos. Soc. 2018; 93: 827-844Crossref PubMed Scopus (35) Google Scholar a fraction of which is found at contact sites between the inner and outer mitochondrial membranes5Gilquin B. Taillebourg E. Cherradi N. Hubstenberger A. Gay O. Merle N. Assard N. Fauvarque M.O. Tomohiro S. Kuge O. Baudier J. The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes.Mol. Cell. Biol. 2010; 30: 1984-1996Crossref PubMed Scopus (83) Google Scholar in complex with TSPO, CYP11A1, and OPA1.6Rone M.B. Midzak A.S. Issop L. Rammouz G. Jagannathan S. Fan J. Ye X. Blonder J. Veenstra T. Papadopoulos V. Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones.Mol. Endocrinol. 2012; 26: 1868-1882Crossref PubMed Scopus (161) Google Scholar ATAD3 has also been shown to interact with mitochondrial nucleoprotein complexes and to play roles in mtDNA organization and replication.2Desai R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar,7He J. Mao C.-C. Reyes A. Sembongi H. Di Re M. Granycome C. Clippingdale A.B. Fearnley I.M. Harbour M. Robinson A.J. et al.The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization.J. Cell Biol. 2007; 176: 141-146Crossref PubMed Scopus (156) Google Scholar,8He J. Cooper H.M. Reyes A. Di Re M. Sembongi H. Litwin T.R. Gao J. Neuman K.C. Fearnley I.M. Spinazzola A. et al.Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.Nucleic Acids Res. 2012; 40: 6109-6121Crossref PubMed Scopus (122) Google Scholar More recently it has been shown to interact with Drp1/DNM1L to support Drp1-induced mitochondrial division,9Zhao Y. Sun X. Hu D. Prosdocimo D.A. Hoppel C. Jain M.K. Ramachandran R. Qi X. ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.Nat. Commun. 2019; 10: 1371Crossref PubMed Scopus (24) Google Scholar a process that drives mtDNA segregation.10Murley A. Lackner L.L. Osman C. West M. Voeltz G.K. Walter P. Nunnari J. ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast.eLife. 2013; 2: e00422Crossref PubMed Scopus (208) Google Scholar,11Lewis S.C. Uchiyama L.F. Nunnari J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells.Science. 2016; 353: aaf5549Crossref PubMed Scopus (268) Google Scholar Concordantly, ATAD3 dysfunction and deficiency have a wide range of effects on mitochondrial structure and function, characterized by disturbed mitochondrial morphology and fission dynamics,3Cooper H.M. Yang Y. Ylikallio E. Khairullin R. Woldegebriel R. Lin K.-L. Euro L. Palin E. Wolf A. Trokovic R. et al.ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.Hum. Mol. Genet. 2017; 26: 1432-1443Crossref PubMed Scopus (33) Google Scholar,6Rone M.B. Midzak A.S. Issop L. Rammouz G. Jagannathan S. Fan J. Ye X. Blonder J. Veenstra T. Papadopoulos V. Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones.Mol. Endocrinol. 2012; 26: 1868-1882Crossref PubMed Scopus (161) Google Scholar loss of cristae,12Peralta S. Goffart S. Williams S.L. Diaz F. Garcia S. Nissanka N. Area-Gomez E. Pohjoismäki J. Moraes C.T. ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels.J. Cell Sci. 2018; 131: jcs217075Crossref PubMed Scopus (28) Google Scholar perturbed mtDNA and cholesterol metabolism, impaired mitochondrial steroidogenesis,2Desai R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar,13Issop L. Fan J. Lee S. Rone M.B. Basu K. Mui J. Papadopoulos V. Mitochondria-associated membrane formation in hormone-stimulated Leydig cell steroidogenesis: role of ATAD3.Endocrinology. 2015; 156: 334-345Crossref PubMed Scopus (84) Google Scholar and decreased levels of some mitochondrial oxidative phosphorylation (OXPHOS) components.12Peralta S. Goffart S. Williams S.L. Diaz F. Garcia S. Nissanka N. Area-Gomez E. Pohjoismäki J. Moraes C.T. ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels.J. Cell Sci. 2018; 131: jcs217075Crossref PubMed Scopus (28) Google Scholar It is not clear whether the disruption to the inner mitochondrial membrane, mtDNA, and OXPHOS complexes are due directly to the absence of ATAD34Baudier J. ATAD3 proteins: brokers of a mitochondria-endoplasmic reticulum connection in mammalian cells.Biol. Rev. Camb. Philos. Soc. 2018; 93: 827-844Crossref PubMed Scopus (35) Google Scholar,12Peralta S. Goffart S. Williams S.L. Diaz F. Garcia S. Nissanka N. Area-Gomez E. Pohjoismäki J. Moraes C.T. ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels.J. Cell Sci. 2018; 131: jcs217075Crossref PubMed Scopus (28) Google Scholar or whether they are consequences of changes to membrane architecture resulting from an altered cholesterol content2Desai R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar,13Issop L. Fan J. Lee S. Rone M.B. Basu K. Mui J. Papadopoulos V. Mitochondria-associated membrane formation in hormone-stimulated Leydig cell steroidogenesis: role of ATAD3.Endocrinology. 2015; 156: 334-345Crossref PubMed Scopus (84) Google Scholar or a combination of the two. We report de novo ATAD3 duplications identified in five unrelated neonates through exome sequencing. Clinical exome sequencing failed to identify any alternative molecular diagnosis potentially causative of the phenotype, which is characterized by seizures (four of the five neonates) and fetal akinesia and contractures (in three case subjects). A clinical summary is shown in Table 1 and clinical case reports are detailed in the Supplemental Note. Informed consent was obtained and all processes adhered to local and national ethical standards. The duplication in the ATAD3 cluster was also detected by arrayCGH for those subjects studied (subjects four and five). The duplication is predicted to be the product of non-alleleic homologous recombination (NAHR) between regions of high sequence homology in ATAD3C and ATAD3A (Figure 1A) and encompasses ATAD3C exons 8–12, ATAD3B, and ATAD3A exons 1–11 (Figures 1B, S1, and S2).Table 1Clinical Features of Individuals with Duplication in ATAD3 Gene ClusterSubject 1Subject 2Subject at at of the and on on matter cerebellar and white matter changes, of on of and of and of on gene mitochondrial gene disease not in a not and sequencing the of the which a kb kb for four due to alternative data not product was in DNA derived from with a de novo and were for all case subjects exome The of the was derived from ATAD3A exon the was derived from ATAD3C 7. The of the duplication identified in four were found to from those identified in the case The duplications are protein are predicted to be differing at a These results are with tandem duplication (subjects and and The duplications are predicted to the of ATAD3A and ATAD3C, ATAD3B, and a fusion composed of ATAD3A and ATAD3C (Figures and We in to the of the sequence of ATAD3A and ATAD3C the genes have an sequence identity of The duplications at a with sequence identity between ATAD3A and ATAD3C (Figure analysis of that the sites are (Figure of ATAD3A and and amino that they are of identical and at (Figure of the variants and the ATPase (Figure the are of a known functional and or a of predicted disorder and was to the of ATAD3A and The was to that ATAD3A is the mitochondrial was in this for these that the fusion is likely to be and and the for We the of ATAD3 a distribution on two of ATAD3A and copy of It is predicted that of ATAD3 be of ATAD3A at copy of the fusion protein (Figure the of the in we a kb product by on from fibroblasts a to ATAD3A and sequencing of this product a sequence identical to the predicted (Figure We found that the of the fusion to that of ATAD3A, two. that fibroblasts the duplication of to controls (Figures and The of the two is ATAD3B and the is attributed to the copy of ATAD3A is not the of the that the protein product is expressed and stable. ATAD3 is an mitochondrial J. Mao C.-C. Reyes A. Sembongi H. Di Re M. Granycome C. Clippingdale A.B. Fearnley I.M. Harbour M. Robinson A.J. et al.The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization.J. Cell Biol. 2007; 176: 141-146Crossref PubMed Scopus (156) Google Scholar and of ATAD3 in fibroblasts of 1 a distribution similar to cells and to the mitochondrial outer membrane protein (Figure both the ATAD3B and the fusion gene protein product to be to the Variants in an ATAD3A in are associated with a in the number of mitochondria and mitochondrial structural T. Yoon W.H. Garone C. Gu S. Coban-Akdemir Z. Eldomery M.K. Posey J.E. Jhangiani S.N. Rosenfeld J.A. Cho M.T. et al.Baylor-Hopkins Center for Mendelian GenomicsUniversity of Washington Center for Mendelian GenomicsRecurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.Am. J. Hum. Genet. 2016; 99: 831-845Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar and bi-allelic ATAD3 cluster deletions have been shown to cause mitochondrial structural and impaired cholesterol metabolism in human R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar we mitochondrial morphology and cholesterol levels in cholesterol by was subjects and was similar to cells with ATAD3 deficiency by bi-allelic ATAD3 cluster R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar (Figures and fibroblasts of and and (Figure cells with an extensive and mitochondrial were also apparent (Figure for DNA indicated that the mitochondria of mtDNA (Figure These are similar to those associated with ATAD3 cluster R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar we that is and mitochondrial morphology and mtDNA organization and causes in cholesterol to the fusion protein, the duplication an copy of whether this have to the phenotype, exome sequence data from all individuals in the were for the of duplications the ATAD3 was identified in this individuals were identified with likely monoallelic duplications the ATAD3 cluster range of 67 of which affected the ATAD3 duplications were found to ATAD3B not were by or clinical were with a metabolic disorder, were the of 1 at clinical and were at the of was not for the and the have not been the of ATAD3B duplications in this that the duplication of ATAD3B and ATAD3B gene is not causative of this severe phenotype, the recombinant gene and protein product by the de novo mutational We have identified two de novo duplications the ATAD3 cluster in five unrelated individuals clinical a metabolic disorder. ATAD3 gene were recently a cause of human T. Yoon W.H. Garone C. Gu S. Coban-Akdemir Z. Eldomery M.K. Posey J.E. Jhangiani S.N. Rosenfeld J.A. Cho M.T. et al.Baylor-Hopkins Center for Mendelian GenomicsUniversity of Washington Center for Mendelian GenomicsRecurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.Am. J. Hum. Genet. 2016; 99: 831-845Abstract Full Text Full Text PDF PubMed Scopus (84) Google R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google H.M. Yang Y. Ylikallio E. Khairullin R. Woldegebriel R. Lin K.-L. Euro L. Palin E. Wolf A. Trokovic R. et al.ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.Hum. Mol. Genet. 2017; 26: 1432-1443Crossref PubMed Scopus (33) Google Scholar for a number of phenotypes and ATAD3A missense variants have been in individuals affected with hypotonia, optic atrophy, neuropathy, cardiomyopathy, and hereditary spastic T. Yoon W.H. Garone C. Gu S. Coban-Akdemir Z. Eldomery M.K. Posey J.E. Jhangiani S.N. Rosenfeld J.A. Cho M.T. et al.Baylor-Hopkins Center for Mendelian GenomicsUniversity of Washington Center for Mendelian GenomicsRecurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.Am. J. Hum. Genet. 2016; 99: 831-845Abstract Full Text Full Text PDF PubMed Scopus (84) Google H.M. Yang Y. Ylikallio E. Khairullin R. Woldegebriel R. Lin K.-L. Euro L. Palin E. Wolf A. Trokovic R. et al.ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.Hum. Mol. Genet. 2017; 26: 1432-1443Crossref PubMed Scopus (33) Google Scholar ATAD3 cluster deletions result in a more severe with pontocerebellar R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google M. in ATAD3A not of 2017; 140: PubMed Scopus Google A.E. Spinazzola A. in ATAD3A not of 2017; 140: PubMed Scopus Google Scholar and in the of case subjects the of similar to bi-allelic ATAD3A T. Yoon W.H. Garone C. Gu S. Coban-Akdemir Z. Eldomery M.K. Posey J.E. Jhangiani S.N. Rosenfeld J.A. Cho M.T. et al.Baylor-Hopkins Center for Mendelian GenomicsUniversity of Washington Center for Mendelian GenomicsRecurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes.Am. J. Hum. Genet. 2016; 99: 831-845Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar These case subjects with a monoallelic ATAD3 gene cluster duplication extend the genotype spectrum of ATAD3-related disorders. The of the neonates with ATAD3 duplications shows with the associated with variation at this locus corneal clouding, cardiomyopathy, hypotonia, white matter changes, fetal and subjects with duplication of four neonates and clinical from was high a severe and with severe 1 and Supplemental The subjects not with of mitochondrial and this the importance of mitochondrial genes in The fusion protein is associated with the severe and is likely It is expressed and (Figures and and has the (Figure The fusion protein from ATAD3A at amino the including a the ATPase (Figure and The is in all and an a that to the of in the T. A.J. in and in and AAA+ Biol. PubMed Scopus Google Scholar missense variants have been at the in (Figure and cause hereditary spastic [MIM: C. S. Lin M. J. N. et spectrum and for hereditary spastic in 2018; PubMed Scopus Google J. N. D. C. D. F. C. A. P. et a protein, is altered in the form of dominant spastic Genet. PubMed Scopus Google Scholar These variants have been shown to result in the loss of ATPase to by Cell Biol. PubMed Scopus Google Scholar to disease through a dominant-negative We that the ATAD3 duplications through the through of a derived from the fusion protein more of ATAD3 (Figure Our data that the of the fusion protein causes this lethal neurological disorder through disruption of mitochondrial and cholesterol metabolism (Figures and the links between and mtDNA the of the cholesterol in mitochondrial with M. O. Reyes A. H. A. Cooper H.M. to a 2015; PubMed Scopus Google Scholar and or cholesterol mtDNA R. Frazier A.E. Durigon R. Patel H. Jones A.W. Dalla Rosa I. Lake N.J. Compton A.G. Mountford H.S. Tucker E.J. et al.ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.Brain. 2017; 140: 1595-1610Crossref PubMed Scopus (53) Google Scholar cholesterol mtDNA ATAD3 has links to cholesterol metabolism through TSPO, CYP11A1, and M.B. Midzak A.S. Issop L. Rammouz G. Jagannathan S. Fan J. Ye X. Blonder J. Veenstra T. Papadopoulos V. Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones.Mol. Endocrinol. 2012; 26: 1868-1882Crossref PubMed Scopus (161) Google Scholar,8He J. Cooper H.M. Reyes A. Di Re M. Sembongi H. Litwin T.R. Gao J. Neuman K.C. Fearnley I.M. Spinazzola A. et al.Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.Nucleic Acids Res. 2012; 40: 6109-6121Crossref PubMed Scopus (122) Google Scholar ATAD3 also with the mitochondrial protein synthesis mtDNA, and mitochondrial J. Mao C.-C. Reyes A. Sembongi H. Di Re M. Granycome C. Clippingdale A.B. Fearnley I.M. Harbour M. Robinson A.J. et al.The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization.J. Cell Biol. 2007; 176: 141-146Crossref PubMed Scopus (156) Google Scholar,8He J. Cooper H.M. Reyes A. Di Re M. Sembongi H. Litwin T.R. Gao J. Neuman K.C. Fearnley I.M. Spinazzola A. et al.Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.Nucleic Acids Res. 2012; 40: 6109-6121Crossref PubMed Scopus (122) Google M. O. Reyes A. H. A. Cooper H.M. to a 2015; PubMed Scopus Google Scholar and is that the mitochondrial nucleoprotein complexes are K. R. S. T. T. M. of Gene in 2015; 10: Full Text Full Text PDF PubMed Scopus Google R. Jones A.W. A. M. H. G. S. et mitochondrial DNA metabolism and Mol. 2018; 10: PubMed Scopus Google Scholar perturbed be the all the associated with ATAD3 deficiency. number variants a in genomic in both and to and rare which is not The high of duplications in the ATAD3 with high sequence homology of the three genes that duplications potentially be the importance of of genomic to a clinical is with a disorder. The high at which this ATAD3 duplication was identified this that for all clinical of severe disorder of for known mitochondrial variants and mitochondrial the ATAD3 locus be for and structural variants. of and have formed a with shared and of which clinical analysis and clinical exome sequencing. on the of has in is a for has in and is a on and to molecular for and genomic The We from is a is by a from the is by a from the of the is by the and of A.S. is by the with a T. is by the is by the of of the of through is by the of and the of and the and and to the Center for Mendelian is by the for the for in the for and disease to the the The and the for of and The by the number of which is by or for with Supplemental and Supplemental and

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