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
  • 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.