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


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.

SUBMITTER: Desai R 

PROVIDER: S-EPMC5445257 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Desai Radha R   Frazier Ann E AE   Durigon Romina R   Patel Harshil H   Jones Aleck W AW   Dalla Rosa Ilaria I   Lake Nicole J NJ   Compton Alison G AG   Mountford Hayley S HS   Tucker Elena J EJ   Mitchell Alice L R ALR   Jackson Deborah D   Sesay Abdul A   Di Re Miriam M   van den Heuvel Lambert P LP   Burke Derek D   Francis David D   Lunke Sebastian S   McGillivray George G   Mandelstam Simone S   Mochel Fanny F   Keren Boris B   Jardel Claude C   Turner Anne M AM   Ian Andrews P P   Smeitink Jan J   Spelbrink Johannes N JN   Heales Simon J SJ   Kohda Masakazu M   Ohtake Akira A   Murayama Kei K   Okazaki Yasushi Y   Lombès Anne A   Holt Ian J IJ   Thorburn David R DR   Spinazzola Antonella A  

Brain : a journal of neurology 20170601 6


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  ...[more]

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