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.

• Authors: Radha Desai, Ann E Frazier, Romina Durigon, Harshil Patel, Aleck W Jones, Ilaria Dalla Rosa, Nicole J Lake, Alison G Compton, Hayley S Mountford, Elena J Tucker, Alice L R Mitchell, Deborah Jackson, Abdul Sesay, Miriam Di Re, Lambert P van den Heuvel, Derek Burke, David Francis, Sebastian Lunke, George McGillivray, Simone Mandelstam, Fanny Mochel, Boris Keren, Claude Jardel, Anne M Turner, P Ian Andrews, Jan Smeitink, Johannes N Spelbrink, Simon J Heales, Masakazu Kohda, Akira Ohtake, Kei Murayama, Yasushi Okazaki, Anne Lombès, Ian J Holt, David R Thorburn, Antonella Spinazzola
• Journal: Brain : a journal of neurology (Brain) Vol. 140 Issue 6 Pg. 1595-1610 (Jun 01 2017) ISSN: 1460-2156 [Electronic] England
• PMID: 28549128 (Publication Type: Journal Article)
• Copyright: © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Chemical References

• ATAD3A protein, human
• ATAD3B protein, human
• ATAD3C protein, human
• DNA, Mitochondrial
• Membrane Proteins
• Mitochondrial Proteins
• Adenosine Triphosphatases
• ATPases Associated with Diverse Cellular Activities

Topics

• ATPases Associated with Diverse Cellular Activities
• Adenosine Triphosphatases (genetics)
• Adult
• Cerebellum (abnormalities, diagnostic imaging, physiopathology)
• Consanguinity
• DNA, Mitochondrial (genetics)
• Developmental Disabilities (diagnostic imaging, genetics, physiopathology)
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Membrane Proteins (genetics)
• Mitochondrial Diseases (diagnostic imaging, genetics, physiopathology)
• Mitochondrial Proteins (genetics)
• Nervous System Malformations (diagnostic imaging, genetics, physiopathology)