neurological syndromes for which there was no cause can be the result of
variations in the gene ATAD3A, discovered a team of scientists from a number of institutions around the world,
including Baylor College of Medicine.
The study, which appears in the American Journal of Human Genetics
today, sheds light on the causes of these diseases and opens the
possibility for developing better diagnostic tools and potential
treatments in the future.
‘Mutations in the gene ATAD3A could be the cause of distinct neurological syndromes. This finding opens the possibility for developing better diagnostic tools and potential treatments in the future.’
"Through collaborative efforts with other teams, we identified a
group of five 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 Dr. Tamar Harel, who was a
genetics fellow at Baylor when she was working on this study and
currently is a geneticist at Hadassah Medical Center in Israel.
To identify the genetic causes of the neurological syndrome, the scientists began what they call a 'fishing expedition.'
"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 Harel.
"The gene became more and more interesting the more Tamar worked
on it," said senior author Dr. James Lupski, Cullen Professor of
Molecular and Human Genetics 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
variants in ATAD3A were associated with neurological syndromes, but not
that they caused them. The scientists then began a collaboration with
co-author Dr. Hugo Bellen, professor and director of the Program in
Developmental Biology and investigator at the Howard Hughes Medical
Institute at Baylor, to combine the human studies with studies in
Drosophila melanogaster, the laboratory fly that has been extensively
Drosophila can serve as an experimental model to
determine the effect gene variants have in a living organism because
most fly genes are conserved in humans, numerous genetic tools are
available, and we can test genes function in tissues.
Co-first author Dr. Wan Hee Yoon, postdoctoral fellow in Bellen lab, developed an ATAD3A disease model in the fly.
"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 Yoon.
Mitochondria are special cellular organelles whose function is to
generate energy, or ATP, for the cell to perform its functions.
Mitochondria are also essential for cellular metabolism because they
generate the 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
Yoon. "Mitophagy is a critical process not only in neurological
diseases, but also in other diseases such as cancer and other metabolic
The scientists also looked at the fibroblasts from their patients
and compared the mitochondria in control and in diseased fibroblasts
and found that those in diseased fibroblasts were inside digestive
vesicles, reflecting mitophagy. Mitophagy in fibroblasts from patients
with ATAD3A variants was significantly higher than the one in control
"The collective data indicate that mutations in ATAD3A can cause
an aberrant phenotype in mitochondria and the flies are actually sick,"
By combining the results of human and fly studies the scientists
feel confident that they can attribute the neurological syndromes
observed in their patients at least in part to malfunctioning variants
of the gene ATAD3A.