Fatal Perinatal Mitochondrial Cardiac Failure Caused by Recurrent De Novo Duplications in the ATAD3 Locus

Frazier, Ann E.; Compton, Alison G.; Kishita, Yoshihito; Hock, Daniella H; Welch, Anne Marie E.; Amarasekera, S. S. C.; Rius, Rocío; Formosa, Luke E.; Imai‐Okazaki, Atsuko; Francis, David; Wang, Min; Lake, Nicole J.; Tregoning, Simone; Jabbari, Jafar S.; Lucattini, Alexis; Nitta, Kazuhiro R.; Ohtake, Akira; Murayama, Kei; Amor, David J.; McGillivray, George; Wong, Flora Yuen-Wait; Knaap, Marjo S. van der; Vermeulen, R. Jeroen; Wiltshire, Esko; Fletcher, Janice M.; Lewis, Barry; Baynam, Gareth; Ellaway, Carolyn; Balasubramaniam, Shanti; Bhattacharya, Kaustuv; Freckmann, Mary Louise; Arbuckle, Susan; Rodriguez, Michael; Taft, Ryan J.; Sadedin, Simon; Cowley, Mark J.; Minoche, André E.; Calvo, Sarah E.; Mootha, Vamsi K.; Ryan, Michael; Okazaki, Yasushi; Stroud, David A.; Simons, Cas; Christodoulou, John; Thorburn, David R.

doi:10.1016/j.medj.2020.06.004

Cited by 48 publications

(64 citation statements)

References 102 publications

(204 reference statements)

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“…Importantly, results from this study provided an additional mutational mechanism for ATAD3 gene cluster variants and highlighted the importance of copy number analysis [57]. Of note, six different de novo duplications in the ATAD3 locus have further been reported in 17 patients from 16 families [10]. Here, an extra copy of the ATAD3B gene and an ATAD3A/ATAD3C fusion gene, whose stable protein product interrupts ATAD3 oligomerization, are formed.…”

Section: Atad3a In Other Diseasesmentioning

confidence: 62%

“…These duplicates are associated with lethal perinatal cardiomyopathy, persistent hyperlactacidemia, corneal clouding or cataracts, and encephalopathy. Specifically, a decrease in oxidation phosphorylation complex I and its activity in heart tissue were observed [10].…”

Section: Atad3a In Other Diseasesmentioning

confidence: 99%

“…As a mitochondrial protein with the capacity to impact essential mitochondrial functions and organization, ATAD3A controls a broad spectrum of physiological and pathological responses, including mitochondrial dynamics, nucleoid organization, signaling transduction, and cholesterol metabolism [7][8][9]. ATAD3A mutations can cause a range of different phenotypes and have been identified as one of the most common causes of lethal infantile mitochondrial disease [10]. Although there have been no or few ATAD3A mutations identified in cancer patients, ATAD3A has nevertheless been implicated in certain types of cancer, where its elevated expression levels have been associated with poor patient outcome.…”

Section: Introductionmentioning

confidence: 99%

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Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer

Lang

Loveless

Teng

2020

IJMS

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Spanning from the mitochondria’s outer surface to the inner membrane, the nuclear-encoded protein ATAD3A maintains vital roles in regulating mitochondrial dynamics, homeostasis, metabolism, and interactions with the endoplasmic reticulum. Recently, elevated levels of ATAD3A have been reported in several types of cancer and to be tightly correlated with cancer development and progression, including increased cancer cell potential of proliferation, metastasis, and resistance to chemotherapy and radiotherapy. In the current review, we reveal ATAD3A as the link between mitochondrial functions and cancer biology and the accumulating evidence presenting ATAD3A as an attractive target for the development of novel cancer therapy to inhibit aberrant cancer metabolism and progression.

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Section: Atad3a In Other Diseasesmentioning

confidence: 62%

Section: Atad3a In Other Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer

Lang

Loveless

Teng

2020

IJMS

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“…Deletions between ATAD3B and ATAD3A lead to a fusion transcript under the regulation of the weaker ATAD3B promoter and thus show decreased expression of an ATAD3B/ATAD3A fusion protein that presumably is sufficient for fetal development but apparently cannot sustain life beyond the neonatal period [ 7 ]. The reciprocal, NAHR-mediated duplication at this locus (between ATAD3C exon 7 and the homologous ATAD3A exon 11, reciprocal to the ATAD3C-ATAD3A deletion described by Harel et al [ 12 ]) results in a fusion gene encoding a protein with multiple alterations at key functional residues [ 18 , 19 ]. We previously hypothesized that the fusion protein acts through a dominant negative mechanism [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

et al. 2021

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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.

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“…Indeed, a variety of pathogenic variants has been reported in this locus, including the (de novo) dominant and recessive SNVs and CNVs [100,[168][169][170][171]. LRS was recently employed to validate the presence of chimeric ATAD3A/ATAD3C gene in one patient with a de novo ATAD3 duplication [172]. As emerging studies argue the higher incidence of ATAD3 as a cause of pediatriconset disease, LRS may help overcome the challenges in assessing its sequence.…”

Section: New Sequencing Technologiesmentioning

confidence: 99%

Genetic basis of mitochondrial diseases

Gusic

2021

FEBS Letters

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Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different genes. The implementation of whole exome sequencing has led to a revolution in their diagnosis, duplicated the number of associated disease genes, and significantly increased the diagnosed fraction. However, the genetic etiology of a substantial fraction of patients exhibiting mitochondrial disorders remains unknown, highlighting limitations in variant detection and interpretation, which calls for improved computational and DNA sequencing methods, as well as the addition of OMICS tools. More intriguingly, this also suggests that some pathogenic variants lie outside of the proteincoding genes and that the mechanisms beyond the Mendelian inheritance and the mtDNA are of relevance. This review covers the current status of the genetic basis of mitochondrial diseases, discusses current challenges and perspectives, and explores the contribution of factors beyond the protein-coding regions and monogenic inheritance in the expansion of the genetic spectrum of disease.

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Fatal Perinatal Mitochondrial Cardiac Failure Caused by Recurrent De Novo Duplications in the ATAD3 Locus

Cited by 48 publications

References 102 publications

Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer

Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

Genetic basis of mitochondrial diseases

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