한빛사 논문
Zheng Yie Yap1,†, Yo Han Park1,†, Saskia B. Wortmann2,3,4,†, Adam C. Gunning5,6, Shlomit Ezer7,8, Sukyeong Lee9, Lita Duraine10, Ekkehard Wilichowski11, Kate Wilson12, Johannes A. Mayr3, Matias Wagner2,13, Hong Li14,15, Usha Kini12, Emily Davis Black14, Kristin G. Monaghan16, James R. Lupski17,18,19,20, Sian Ellard5,6, Dominik S. Westphal2, Tamar Harel7,8,* and Wan Hee Yoon1,*
1Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. 2Institute of Human Genetics, Technical University Munich, Munich, Germany. 3University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria. 4Radboud Centre for Mitochondrial Medicine (RCMM), Amalia Children’s Hospital, Nijmegen, The Netherlands. 5Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK. 6Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX2 5DW, UK. 7Department of Genetics, Hadassah Medical Center, POB 12000, 9112001 Jerusalem, Israel. 8Faculty of Medicine, Hebrew University of Jerusalem, POB 12000, 9112001 Jerusalem, Israel. 9Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA. 10Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX, USA. 11Department of Pediatrics and Pediatric Neurology, University Medical Center Göttingen, Georg-August-Universität Göttingen, Göttingen, Germany. 12Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 13Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany. 14Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA. 15Department of Pediatrics, School of Medicine, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA. 16GeneDx Inc., Gaithersburg, MD, USA. 17Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 18Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. 19Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. 20Texas Children’s Hospital, Houston, TX, USA.
*Correspondence
†Zheng Yie Yap, Yo Han Park and Saskia B. Wortmann contributed equally to this work.
Abstract
Background
ATPase 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.
Methods
To 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.
Results
We 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.
Conclusion
Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.
논문정보
관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기