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| Status |
Public on Jun 23, 2017 |
| Title |
Deletions in the ATAD3 gene cluster cause cerebellar developmental defects with mitochondrial DNA abnormalities owing to local cholesterol insufficiency |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The DNA in mitochondria is associated with the inner of two membranes and it co-fractionates with the limited amount of cholesterol in the organelles. However, the effects of mitochondrial cholesterol deficiency are largely unknown, and mitochondrial disorders relating to this area of cell metabolism have not been reported hitherto. Using detailed SNP array analysis we have identified patients with impaired cerebellar development and neurological dysfunction who have large deletions in the locus encoding the ATAD3A, ATAD3B and ATAD3C genes. Patient cells with inherited ATAD3 defects display aberrant mitochondrial DNA organization and synthesis associated with disrupted cholesterol metabolism. Moreover drug-induced perturbations of cholesterol metabolism cause mitochondrial DNA disorganization in control cells. The interdependence of mitochondria and cholesterol homeostasis is further corroborated by the presence of mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann Pick type C disease. Thus, we conclude, mitochondria are fully integrated in the circuitry of cellular cholesterol homeostasis, in which ATAD3 plays a critical role, and the dual problem of perturbed cholesterol homeostasis and mitochndrila dysfunction may be widespread in neurological and neurodegenerative diseases.
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| Overall design |
We designed the experiment to compare the expression profiles of cells carrying deletions in the ATAD3 gene cluster (ATAD3CAS & ATAD3F) with that of a normal control cell line. Because we suspected that cholesterol metabolism would be altered by ATAD3 deficiency we also prepared RNA from the same three cell lines treated with a drug, pravastatin, that inhibits the rate limiting step of cholesterol synthesis, to determine if the drug produced similar effects on gene expression to ATAD3 deficiency. In practice, pravastatin had almost no signficant effects (FDR 0.05) on any of the cells and none related to cholesterol homeostasis, indicating the drug does not act at the level of gene expression. This proved convenient as two RNA samples from ATAD3CAS failed QC, but the ATAD3CAS + pravastatin versus control (with or without pravastatin) provided additional replicates and displayed almost identical differences to ATAD3CAS (no drug) vs Control.
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| Contributor(s) |
Desai R, Frazier AE, Durigon R, Patel H, Rosa ID, Lake NJ, Mitchell A, Jackson D, Sesay AK, Re MD, Spelbrink JN, Burke D, McGillivray G, Mandelstam S, Compton A, Mountford H, Francis D, Mochel F, Keren B, Jardel C, Turner AM, van den Heuvel LP, Smeitink J, Heales SJ, Lombès A, Holt IJ, Thorburn DR, Spinazzola A |
| Citation(s) |
28549128 |
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| Submission date |
Sep 07, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
ian james holt |
| E-mail(s) |
Ian.Holt@crick.ac.uk
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| Phone |
+ 44 20 8816 2273
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| Organization name |
Crick Institute
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| Street address |
1 Midland Road
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| City |
London |
| ZIP/Postal code |
NW1 1AT |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (15)
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| GSM2305478 |
Patient 1 ATAD3CAS biological replicate 1 |
| GSM2305479 |
Patient 2 ATAD3F biological replicate 1 |
| GSM2305480 |
Patient 2 ATAD3F biological replicate 2 |
| GSM2305481 |
Patient 2 ATAD3F biological replicate 3 |
| GSM2305482 |
Control biological replicate 1 |
| GSM2305483 |
Control biological replicate 2 |
| GSM2305484 |
Patient 1 ATAD3CAS Pravastatin biological replicate 1 |
| GSM2305485 |
Patient 1 ATAD3CAS Pravastatin biological replicate 2 |
| GSM2305486 |
Patient 1 ATAD3CAS Pravastatin biological replicate 3 |
| GSM2305487 |
Patient 2 ATAD3F Pravastatin biological replicate 1 |
| GSM2305488 |
Patient 2 ATAD3F Pravastatin biological replicate 2 |
| GSM2305489 |
Patient 2 ATAD3F Pravastatin biological replicate 3 |
| GSM2305490 |
Control Pravastatin biological replicate 1 |
| GSM2305491 |
Control Pravastatin biological replicate 2 |
| GSM2305492 |
Control Pravastatin biological replicate 3 |
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| Relations |
| BioProject |
PRJNA342177 |
| SRA |
SRP087536 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE86550_allSamples_RNASeq_RSEM_TPM.tsv.gz |
1.1 Mb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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