About ATAD3A Gene Mutations

The ATAD3A gene

 

The ATAD3A gene is located on chromosome 1p36.33 and provides the instructions for making a protein that works in the mitochondria—the tiny “power plants” within our cells where cellular energy is generated through metabolic reactions.
Mitochondria are especially important for the brain, eye, nerve, heart, and muscles, which need a lot of energy to function properly. ATAD3A belongs to our nuclear DNA (nDNA), which contains most of the genetic information that makes us who we are. Scientists are still learning exactly how ATAD3A works, but we know
it helps mitochondria maintain their shape, communicate with other cell parts, and manage important molecules like cholesterol.

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How ATAD3A gene change causes disease

 

There are different kinds of changes, or mutations, in the ATAD3A gene that can lead to disease:
 

1. De novo variants: Some mutations happen for the first time in a child (called de novo mutations). These are new genetic changes that happen by chance in the egg or sperm. These often act in a dominant way, meaning a single altered copy of the gene is enough to cause symptoms.
    

2. Recessive or biallelic loss-of-function (LoF) variants: These occur when both copies of the ATAD3A gene (one from each parent) are changed or missing.

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Harel-Yoon Syndrome (HAYOS)

 

​When ATAD3A mutations cause a specific set of shared symptoms, the condition is known as Harel-Yoon syndrome (HAYOS). The syndrome was first described in 2016 by Dr. Tamar Harel and Dr. Wan Hee Yoon, who identified a group of children with similar clinical features caused by ATAD3A mutations. HAYOS is now recognized as a neurodevelopmental disorder that primarily affects the brain and nervous system.
Harel-Yoon syndrome is characterized by a spectrum of symptoms and characteristics which may include developmental delays, impacts on a person’s brain, eyes, muscles, heart, and/or digestive systems.

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Resources

 

The ATAD3A Patient Advocacy Alliance is currently developing resources for newly-diagnosed patients, families and clinicians with guidance from our Medical Advisory Board. These materials will be added to this page as they are finalized.

Here are some resources that describe ATAD3A mutations and Harel-Yoon syndrome:
 

• Genetic and Rare Diseases Information Center (GARD)

• Orphanet
   

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References: ​

1. Brugel, M., Kiesel, A.S., Haack, T.B., and Peralta, S. (2024). Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models. Front Neurosci 18, 1496142. 10.3389/fnins.2024.1496142.

2. Harel, T., Yoon, W.H., Garone, C., Gu, S., Coban-Akdemir, Z., Eldomery, M.K., Posey, J.E., Jhangiani, S.N., Rosenfeld, J.A., Cho, M.T., et al. (2016). Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. Am J Hum Genet 99, 831-845. 10.1016/j.ajhg.2016.08.007.

3. Cooper, H.M., Yang, Y., Ylikallio, E., Khairullin, R., Woldegebriel, R., Lin, K.L., Euro, L., Palin, E., Wolf, A., Trokovic, R., et al. (2017). ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. Hum Mol Genet 26, 1432-1443. 10.1093/hmg/ddx042.

4. Munoz-Oreja, M., Sandoval, A., Bruland, O., Perez-Rodriguez, D., Fernandez-Pelayo, U., de Arbina, A.L., Villar-Fernandez, M., Hernandez-Eguiazu, H., Hernandez, I., Park, Y., et al. (2024). Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation. Brain 147, 1899-1913. 10.1093/brain/awae018.

5. Yap, Z.Y., Park, Y.H., Wortmann, S.B., Gunning, A.C., Ezer, S., Lee, S., Duraine, L., Wilichowski, E., Wilson, K., Mayr, J.A., et al. (2021). Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes. Genome Med 13, 55. 10.1186/s13073-021-00873-3.

6. Desai, R., Frazier, A.E., Durigon, R., Patel, H., Jones, A.W., Dalla Rosa, I., Lake, N.J., Compton, A.G., Mountford, H.S., Tucker, E.J., et al. (2017). ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain 140, 1595-1610.10.1093/brain/awx094.