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

Drosophila studies contributed to -- another -- study that identifies a human disease gene

Ansar M, Chung HL, Taylor RL, Nazir A, Imtiaz S, Sarwar MT, Manousopoulou A, Makrythanasis P, Saeed S, Falconnet E, Guipponi M, Pournaras CJ, Ansari MA, Ranza E, Santoni FA, Ahmed J, Shah I, Gul K, Black GC, Bellen HJ, Antonarakis SE. Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts. Am J Hum Genet. 2018 Oct 4;103(4):568-578. PMID: 30290152; PMCID: PMC6174361.

From the abstract: "Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP ... The phenotypes of all affected individuals include infantile-onset cataracts. RNAi-mediated knockdown of the Drosophila ortholog still life (sif), enriched in lens-secreting cells, affects the development of these cells as well as the localization of E-cadherin, alters the distribution of septate junctions in adjacent cone cells, and leads to a ∼50% reduction in electroretinography amplitudes in young flies. ... We therefore conclude that DNMBP loss-of-function variants cause infantile-onset cataracts in humans."

Big thank you to the US NIH Office of Research Infrastructure Programs (ORIP) for support of projects that generated fly stocks and other resources used in this study.

Mitochondrial disorders. New fly disease model. Recent report.

Studies in Drosophila contribute to characterization of a human gene newly implicated in disease. Table 2 of the paper presents a comparison of the human disease and fly knockdown phenotypes.

van Bon BW, Oortveld MA, Nijtmans LG, Fenckova M, Nijhof B, Besseling J, Vos M, Kramer JM, de Leeuw N, Castells-Nobau A, Asztalos L, Viragh E, Ruiter M, Hofmann F, Eshuis L, Collavin L, Huynen MA, Asztalos Z, Verstreken P, Rodenburg RJ, Smeitink JA, de Vries BB, Schenck A. CEP89 is required for mitochondrial metabolism and neuronal function in man and fly. Hum Mol Genet. 2013 Apr 10. PMID: 23575228.