期刊
BRAIN
卷 140, 期 -, 页码 1595-1610出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx094
关键词
mitochondrial DNA; mitochondrial disease; cerebellar hypoplasia; ATAD3; cholesterol
资金
- Australian National Health and Medical Research Council (NHMRC) [1068409, 1107094]
- Australian Mitochondrial Disease Foundation
- NHMRC Principal Research Fellowship [1102896]
- NHMRC Early Career Fellowship [1054432]
- to E.J.T.), an NHMRC scholarship (H.S.M.), an Australian Postgraduate Victorian Government's Operational Infrastructure Support Program
- Medical Research Council
- FRM (Fondation pour la Recherche Medicale) [DPM20121125550]
- Association Francaise contre les Myopathies (AFM)
- Association contre les Maladies Mitochondriales (AMMi)
- CSBB grant from NWO-ALW [853.00.130]
- Strategic Research Center in Private Universities grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED)
- [MC_PC_13029]
- BBSRC [BB/F012802/1] Funding Source: UKRI
- MRC [MC_PC_13029/2, MC_U105663140, MC_PC_13029/1, MC_UP_1202/14] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F012802/1] Funding Source: researchfish
- Medical Research Council [MC_UP_1202/14, MC_PC_13029, 1098609, MC_PC_13029/1, MC_PC_13029/2, MC_U105663140] Funding Source: researchfish
- The Francis Crick Institute [10002] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1068409] Funding Source: NHMRC
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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