Back to Search
Start Over
Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes
- Source :
- American journal of human genetics. 99(4)
- Publication Year :
- 2016
-
Abstract
- ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
- Subjects :
- 0301 basic medicine
Male
Developmental Disabilities
MFN2
Mitochondrion
medicine.disease_cause
ATAD3A
DNM1L
0302 clinical medicine
Mitophagy
whole-exome sequencing
Child
Genetics (clinical)
Genetics
Adenosine Triphosphatases
Neurons
cardiomyopathy
CNV
de novo variant
dominant negative
mitochondrial dynamics
neuropathy
optic atrophy
ATPases Associated with Diverse Cellular Activities
Adult
Animals
Axons
Cardiomyopathies
Child, Preschool
DNA Copy Number Variations
Drosophila melanogaster
Female
Fibroblasts
Homozygote
Humans
Infant
Infant, Newborn
Membrane Proteins
Mitochondria
Mitochondrial Proteins
Muscle Hypotonia
Muscles
Nervous System Diseases
Optic Atrophy
Phenotype
Polymorphism, Single Nucleotide
Syndrome
Young Adult
Alleles
Mutation
Single Nucleotide
Mitochondrial Membrane Protein
Non-allelic homologous recombination
Biology
Article
03 medical and health sciences
Genetic
mitochondrial dynamic
medicine
Polymorphism
Preschool
Newborn
Molecular biology
030104 developmental biology
Nucleoid organization
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15376605
- Volume :
- 99
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- American journal of human genetics
- Accession number :
- edsair.doi.dedup.....0e8bd8057c91d16ff4fdd8ccb34f6663