Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

TitleFunctional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.
Publication TypeJournal Article
Year of Publication2021
AuthorsYap, ZYie, Park, YHan, Wortmann, SB, Gunning, AC, Ezer, S, Lee, S, Duraine, L, Wilichowski, E, Wilson, K, Mayr, JA, Wagner, M, Li, H, Kini, U, Black, EDavis, Monaghan, KG, Lupski, JR, Ellard, S, Westphal, DS, Harel, T, Yoon, WHee
JournalGenome Med
Date Published2021 Apr 12
KeywordsAdolescent, Alleles, Amino Acid Sequence, Animals, ATPases Associated with Diverse Cellular Activities, Autophagy, Computer Simulation, Drosophila, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Locomotion, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Mitophagy, Mutation, Missense, Neurogenesis, Neurons, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Young Adult

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.

Alternate JournalGenome Med
PubMed ID33845882
PubMed Central IDPMC8042885
Grant ListR35 NS105078 / NS / NINDS NIH HHS / United States
P20 GM103636 / GM / NIGMS NIH HHS / United States

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