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

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

  • Am J Hum Genet. 2016 Oct 6;99(4):831-845. doi: 10.1016/j.ajhg.2016.08.007.
Tamar Harel 1,  Wan Hee Yoon 2,  Caterina Garone 3,  Shen Gu 4,  Zeynep Coban-Akdemir 4,  Mohammad K Eldomery 4,  Jennifer E Posey 4,  Shalini N Jhangiani 5,  Jill A Rosenfeld 6,  Megan T Cho 7,  Stephanie Fox 8,  Marjorie Withers 4,  Stephanie M Brooks 9,  Theodore Chiang 10,  Lita Duraine 2,  Serkan Erdin 11,  Bo Yuan 6,  Yunru Shao 4,  Elie Moussallem 4,  Costanza Lamperti 12,  Maria A Donati 13,  Joshua D Smith 14,  Heather M McLaughlin 7,  Christine M Eng 6,  Magdalena Walkiewicz 6,  Fan Xia 6,  Tommaso Pippucci 15,  Pamela Magini 16,  Marco Seri 17,  Massimo Zeviani 12,  Michio Hirano 18,  Jill V Hunter 19,  Myriam Srour 20,  Stefano Zanigni 21,  Richard Alan Lewis 22,  Donna M Muzny 10,  Timothy E Lotze 23,  Eric Boerwinkle 24,  Baylor-Hopkins Center for Mendelian Genomics,  University of Washington Center for Mendelian Genomics,  Richard A Gibbs 5,  Scott E Hickey 9,  Brett H Graham 4,  Yaping Yang 6,  Daniela Buhas 25,  Donna M Martin 26,  Lorraine Potocki 27,  Claudio Graziano 15,  Hugo J Bellen 28,  James R Lupski 29
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
  • 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: [email protected].
PMID: 27640307 DOI: 10.1016/j.ajhg.2016.08.007
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.

Figures