Drosophila studies help in characterization of disease-associated variants in ATAD3A

Genome Med. 2021 Apr 12;13(1):55. doi: 10.1186/s13073-021-00873-3.

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

Yap ZY, Park YH, Wortmann SB, Gunning AC, Ezer S, Lee S, Duraine L, Wilichowski E, Wilson K, Mayr JA, Wagner M, Li H, Kini U, Black ED, Monaghan KG, Lupski JR, Ellard S, Westphal DS, Harel T, Yoon WH

From the abstract:

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. ... 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 ... 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. ... We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. ... Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation ... Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles ... Leu77Val and Arg170Trp
are partial loss-of-function alleles that cause progressive locomotion defects ... Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

DOI: 10.1186/s13073-021-00873-3
PMID: 33845882