title: Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.
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 borWTresulted 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: harel.tamar@gmail.com.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: 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.
authors.forename: Wan Hee
authors.initials: WH
authors.lastname: Yoon
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge CB2 OXY, UK.
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Coban-Akdemir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Eldomery
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: 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.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Medical Genetics Department, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fox
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Withers
authors.affiliation: Department of Pediatrics, The Ohio State University College of Medicine, Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Brooks
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Chiang
authors.affiliation: 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.
authors.forename: Lita
authors.initials: L
authors.lastname: Duraine
authors.affiliation: 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.
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yunru
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Elie
authors.initials: E
authors.lastname: Moussallem
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology-IRCCS, Milan 20126, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: Metabolic and Muscular Unit, Meyer Children's Hospital, University of Florence, Florence 50132, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Donati
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: McLaughlin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Medical Genetics Unit, Department of Medical and Surgical Science, University of Bologna, Bologna 40138, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Magini
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology-IRCCS, Milan 20126, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.affiliation: Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.affiliation: Department of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.affiliation: Functional MR Unit, Policlinico S. Orsola - Malpighi, Bologna 40138, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna 40123, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanigni
authors.affiliation: 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.
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatric Neurology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Lotze
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Pediatrics, The Ohio State University College of Medicine, Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Hickey
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Medical Genetics Department, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada; Human Genetics Department, McGill University, Montreal, QC H3A 0G4, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Buhas
authors.affiliation: 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.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.affiliation: Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Graziano
authors.affiliation: 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.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000818:Animals; D001369:Axons / Q000473:pathology; D009202:Cardiomyopathies / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics; D009132:Muscles / Q000473:pathology; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009896:Optic Atrophy / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013577:Syndrome; D055815:Young Adult
chemical_list: C549686:ATAD3A protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: ATAD3A; CNV; cardiomyopathy; de novo variant; dominant negative; mitochondrial dynamics; neuropathy; optic atrophy; whole-exome sequencing