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    ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism

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    42
    Author
    Desai, R; Frazier, AE; Durigon, R; Patel, H; Jones, AW; Rosa, ID; Lake, NJ; Compton, AG; Mountford, HS; Tucker, EJ; ...
    Date
    2017-06-01
    Source Title
    Brain: a journal of neurology
    Publisher
    OXFORD UNIV PRESS
    University of Melbourne Author/s
    Lake, Nicole; Mandelstam, Simone; Lunke, Sebastian; Thorburn, David; Frazier, Ann; Compton, Alison; Mountford, Hayley; Tucker, Elena
    Affiliation
    Clinical Pathology
    Medicine and Radiology
    Paediatrics (RCH)
    Metadata
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    Document Type
    Journal Article
    Citations
    Desai, R., Frazier, A. E., Durigon, R., Patel, H., Jones, A. W., Rosa, I. D., Lake, N. J., Compton, A. G., Mountford, H. S., Tucker, E. J., Mitchell, A. L. R., Jackson, D., Sesay, A., Di Re, M., van den Heuvel, L. P., Burke, D., Francis, D., Lunke, S., McGillivray, G. ,... Spinazzola, A. (2017). ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. BRAIN, 140 (6), pp.1595-1610. https://doi.org/10.1093/brain/awx094.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259482
    DOI
    10.1093/brain/awx094
    Abstract
    Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data. We report deletions that generate chimeric ATAD3B/ATAD3A fusion genes in individuals from four unrelated families with fatal congenital pontocerebellar hypoplasia, whereas a case with genomic rearrangements affecting the ATAD3C/ATAD3B genes on one allele and ATAD3B/ATAD3A genes on the other displays later-onset encephalopathy with cerebellar atrophy, ataxia and dystonia. Fibroblasts from affected individuals display mitochondrial DNA abnormalities, associated with multiple indicators of altered cholesterol metabolism. Moreover, drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization in control cells, while mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol. These data demonstrate the integration of mitochondria in cellular cholesterol homeostasis, in which ATAD3 plays a critical role. The dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction could be widespread in neurological and neurodegenerative diseases.

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