Gene Abnormality Found to Underlie Rare Neurological Disease

Researchers have discovered that malfunctioning variants of a gene encoding a mitochondrial protein results in a group of related neurological syndromes classified as conditions of unknown origin. The study sheds new light on causes of such diseases and opens a door for developing better diagnostic tools and treatments.

Led by researchers from Baylor College of Medicine (Houston, TX, USA), the study has shown that this group of syndromes can result from variations in the gene ATAD3A encoding for the ATPase family AAA-domain containing protein 3A (ATAD3A), a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism.

“Through collaborative efforts with other teams, we identified a group of 5 non-related individuals with similar neurological characteristics of unknown origin. They had in common global developmental delay, low muscular tone and visual, neurological and heart problems,” said co-first author Tamar Harel, a genetics fellow at Baylor while working on this study, currently a geneticist at Hadassah Medical Center (Israel).

To investigate potential genetic causes “we sequenced the genes of each of the patients and by a process of comparison and elimination we found that the patients had in common the same new variant in this gene ATAD3A, but their parents did not. This indicated that this was a new mutation that had occurred in the children. We started as a fishing expedition but then we found this gene and decided to study it further,” said Dr. Harel.

“The gene became more and more interesting the more Tamar worked on it,” said senior author James Lupski, professor at Baylor, “Tamar was able to find that some patients had mutations in one copy of the gene, and this was enough to cause disease, while other patients had to have mutations in both copies of the gene to get disease. She also found families with one single error in the gene and others in which the disease was associated with a genomic copy number variant.”

Nevertheless, the human studies only revealed that the new ATAD3A variants were associated with neurological syndromes, not that they caused them. The scientists began a collaboration with co-author Hugo Bellen, professor at the Howard Hughes Medical Institute at Baylor, to combine the human studies with studies in the fruit fly Drosophila melanogaster as experimental model to help determine effects of the gene variants.

Co-first author Wan Hee Yoon, postdoctoral fellow in the Bellen lab, developed an ATAD3A disease model in D. melanogaster: “I expressed the normal, wild type protein in motor neurons and muscles of a group of flies, and the protein carrying the gene variant in the same tissues in other flies. We found that expression of the variant protein caused a dramatic decrease in the number of mitochondria, as well as an increase in mitophagy,” said Dr. Yoon.

In addition to generating energy as ATP, mitochondria are also essential for cellular metabolism as they generate building blocks needed to synthesize proteins and lipids. “The cell has a way to maintain its mitochondria healthy. One way is fusion and fission which allows cells to regenerate worn down mitochondria or to eliminate those that are not functional by digesting them and reusing their components, a process called mitophagy,” said Dr. Yoon, “Mitophagy is a critical process not only in neurological diseases, but also in other diseases such as cancer and other metabolic diseases.”

The scientists also examined fibroblasts from the patients. Comparing mitochondria in control versus in diseased fibroblasts they found that those in diseased fibroblasts were inside digestive vesicles, reflecting mitophagy. Mitophagy in fibroblasts from patients with ATAD3A variants was significantly higher than in control fibroblasts.

“The collective data indicate that mutations in ATAD3A can cause an aberrant phenotype in mitochondria and the flies are actually sick,” said Dr. Yoon. Combining the results of the human and fly studies increases confidence that the neurological syndromes observed in the study patients can be attributed at least in part to malfunctioning ATAD3A variants.

The study, by Harel T, Yoon WH, et al, was published online ahead of print September 15, 2016, in the American Journal of Human Genetics.

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