Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

Genome Medicine

Zheng Yie Yap¹  Yo Han Park¹  Wan Hee Yoon¹  Tamar Harel²  Shlomit Ezer²  Emily Davis Black³  Hong Li⁴  James R. Lupski⁵  Ekkehard Wilichowski⁶  Adam C. Gunning⁷  Sian Ellard⁷  Kristin G. Monaghan⁸  Dominik S. Westphal⁹  Matias Wagner^1,10  Saskia B. Wortmann^1,11  Lita Duraine^1,12  Kate Wilson^1,13  Usha Kini^1,13  Johannes A. Mayr^1,14  Sukyeong Lee^1,15 

[1] Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 73104, Oklahoma City, OK, USA;Department of Genetics, Hadassah Medical Center, POB 12000, 9112001, Jerusalem, Israel;Faculty of Medicine, Hebrew University of Jerusalem, POB 12000, 9112001, Jerusalem, Israel;Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA;Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA;Department of Pediatrics, School of Medicine, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA;Texas Children’s Hospital, Houston, TX, USA;Department of Pediatrics and Pediatric Neurology, University Medical Center Göttingen, Georg-August-Universität Göttingen, Göttingen, Germany;Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, EX2 5DW, Exeter, UK;Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, EX2 5DW, Exeter, UK;GeneDx Inc., Gaithersburg, MD, USA;Institute of Human Genetics, Technical University Munich, Munich, Germany;Institute of Human Genetics, Technical University Munich, Munich, Germany;Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany;Institute of Human Genetics, Technical University Munich, Munich, Germany;University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria;Radboud Centre for Mitochondrial Medicine (RCMM), Amalia Children’s Hospital, Nijmegen, The Netherlands;Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX, USA;Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK;University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria;Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA;

关键词: ATAD3A;    Mitochondria;    Disease;    Autosomal recessive;    Autophagy;    Neurogenesis;    Drosophila;    AAA+ protein;   

DOI  :  10.1186/s13073-021-00873-3

来源: Springer

【 摘 要 】

BackgroundATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.MethodsTo expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.ResultsWe report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.ConclusionOur findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

【 授权许可】

CC BY