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

Rajesh K Desai ,Lambert P Van Den Heuvel,Yasushi Okazaki,David Francis,Nicole J Lake,Claude Jardel,Akira Ohtake,Elena J Tucker,Johannes N Spelbrink,Sebastian Lunke,Miriam Di Re,Romina Durigon,Hayley S Mountford,David R Thorburn,Simone Mandelstam,Anne Lombès,Kei Murayama,Derek Burke,Antonella Spinazzola,George Mcgillivray,Harshil Patel,Alison G Compton,Masakazu Kohda,Ilaria Dalla Rosa,Fanny Mochel,Ann E Frazier,Boris Keren,Peter Ian Andrews ,Ian Holt ,Alice Mitchell ,Anne Turner ,Jan A.m Smeitink ,Simon Heales ,Deborah J Jackson ,Aleck W.e Jones ,Abdul Karim Sesay

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.

Highlights

Mutations in mtDNA and in the nuclear-encoded factors required for mtDNA maintenance and expression result in a broad range of human diseases, most of which affect the CNS (Area-Gomez and Schon, 2014)
Believed to float free in the mitochondrial matrix unfettered by packaging proteins, it is established that mtDNA is organized in nucleoprotein complexes, called nucleoids, which are associated with the inner mitochondrial membrane (Spelbrink, 2010)
We demonstrated that ATAD3 deficiency causes aberrant mtDNA organization and is associated with elevated free cholesterol and increased expression of genes involved in cholesterol metabolism

Summary

Introduction

Mutations in mtDNA and in the nuclear-encoded factors required for mtDNA maintenance and expression result in a broad range of human diseases, most of which affect the CNS (Area-Gomez and Schon, 2014). Believed to float free in the mitochondrial matrix unfettered by packaging proteins, it is established that mtDNA is organized in nucleoprotein complexes, called nucleoids, which are associated with the inner mitochondrial membrane (Spelbrink, 2010). The apparatus mediating the interaction with the inner mitochondrial membrane is predicted to have a role in mtDNA organization and distribution, and its dysfunction might result in alteration of nucleoid structure and composition, which in turn could adversely affect mtDNA segregation and membrane architecture, leading to disease. A candidate to participate in such interactions is ATAD3, ATPase family, AAA + domain containing 3, which was assigned as a detergent-resistant component of mitochondrial nucleoids with potential roles in mtDNA organization and segregation (He et al, 2007) and enhancing hormonalinduced steroidogenesis (Issop et al, 2015).

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