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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

  • 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: harel.tamar@gmail.com.
  • 2Department 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.
  • 3MRC Mitochondrial Biology Unit, Cambridge CB2 OXY, UK.
  • 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5Department 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.
  • 6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7GeneDx, Gaithersburg, MD 20877, USA.
  • 8Medical Genetics Department, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada.
  • 9Department of Pediatrics, The Ohio State University College of Medicine, Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
  • 10Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 11Center 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.
  • 12Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology-IRCCS, Milan 20126, Italy.
  • 13Metabolic and Muscular Unit, Meyer Children's Hospital, University of Florence, Florence 50132, Italy.
  • 14Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 15Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy.
  • 16Medical Genetics Unit, Department of Medical and Surgical Science, University of Bologna, Bologna 40138, Italy.
  • 17Medical 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.
  • 18Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
  • 19Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
  • 20Department of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada.
  • 21Functional MR Unit, Policlinico S. Orsola - Malpighi, Bologna 40138, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna 40123, Italy.
  • 22Department 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.
  • 23Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatric Neurology, Texas Children's Hospital, Houston, TX 77030, USA.
  • 24Human 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.
  • 25Medical Genetics Department, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada; Human Genetics Department, McGill University, Montreal, QC H3A 0G4, Canada.
  • 26Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, 48109; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • 27Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 28Department 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.
  • 29Department 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
[Available on 2017-04-06]
DOI:
10.1016/j.ajhg.2016.08.007
[PubMed - in process]
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