Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

• Type of Material: Article
• Authors: Zheng Yie Yap, Oklahoma Medical Research Foundation; Yo Han Park, Oklahoma Medical Research Foundation; Saskia B. Wortmann, Technical University of Munich; Adam C. Gunning, Royal Devon & Exeter NHS Foundation Trust; Shlomit Ezer, Hadassah Medical Center; Sukyeong Lee, Baylor College of Medicine; Lita Duraine, Baylor College of Medicine; Ekkehard Wilichowski, Georg August University Gottingen; Kate Wilson, Oxford University Hospitals NHS Trust; Johannes A. Mayr, Paracelsus Medical University; Matias Wagner, Technical University of Munich; Hong Li, Emory University; Usha Kini, Oxford University Hospitals NHS Trust; Emily Davis Black, Emory University; Kristin G. Monaghan, GeneDx Inc; James R. Lupski, Baylor College of Medicine; Sian Ellard, Royal Devon & Exeter NHS Foundation Trust; Dominik S. Westphal, Technical University of Munich; Tamar Harel, Hadassah Medical Center; Wan Hee Yoon, Oklahoma Medical Research Foundation
• Language: English
• Date: 2021-04-12
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13073-021-00873-3
• Title of Journal or Parent Work: Genome Medicine
• Volume: 13
• Issue: 1
• Start Page: 55
• End Page: 55
• Grant/Funding Information: TH is supported by the Israel Science Foundation grant 1663/17. WY is supported by the National Institute of General Medical Sciences of the National Institutes of Health through grant 5 P20 GM103636-08.; SBW is supported by the Anniversary Fund of the Oesterreichische Nationalbank (OeNB, #18023).; JRL is supported by the US National Institute of Neurological Disorders and Stroke (R35NS105078).
• Keywords: Life Sciences & Biomedicine; Neurogenesis; AAA plus protein; Disease; Drosophila; ATAD3A; Autosomal recessive; Science & Technology; Mitochondria; Genetics & Heredity; Autophagy
• Research Categories: Biology, Neuroscience; Biology, Genetics; Chemistry, Biochemistry; Biology, Molecular

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.