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Am J Hum Genet. 2016 Oct 6;99(4):831-845. doi: 10.1016/j.ajhg.2016.08.007. Epub 2016 Sep 15.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: harel.tamar@gmail.com.
2
Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
3
MRC Mitochondrial Biology Unit, Cambridge CB2 OXY, UK.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
GeneDx, Gaithersburg, MD 20877, USA.
8
Medical Genetics Department, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada.
9
Department of Pediatrics, The Ohio State University College of Medicine, Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
10
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
11
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
12
Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology-IRCCS, Milan 20126, Italy.
13
Metabolic and Muscular Unit, Meyer Children's Hospital, University of Florence, Florence 50132, Italy.
14
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
15
Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy.
16
Medical Genetics Unit, Department of Medical and Surgical Science, University of Bologna, Bologna 40138, Italy.
17
Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy; Medical Genetics Unit, Department of Medical and Surgical Science, University of Bologna, Bologna 40138, Italy.
18
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
19
Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
20
Department of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada.
21
Functional MR Unit, Policlinico S. Orsola - Malpighi, Bologna 40138, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna 40123, Italy.
22
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
23
Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatric Neurology, Texas Children's Hospital, Houston, TX 77030, USA.
24
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, The University of Texas Health Science Center, Houston, TX 77030, USA.
25
Medical Genetics Department, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada; Human Genetics Department, McGill University, Montreal, QC H3A 0G4, Canada.
26
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, 48109; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
27
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
28
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
29
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

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.

KEYWORDS:

ATAD3A; CNV; cardiomyopathy; de novo variant; dominant negative; mitochondrial dynamics; neuropathy; optic atrophy; whole-exome sequencing

PMID:
27640307
PMCID:
PMC5065660
DOI:
10.1016/j.ajhg.2016.08.007
[Indexed for MEDLINE]
Free PMC Article

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