Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism

Gunning, Adam C.; Strucinska, Klaudia; Oreja, Mikel Muñoz; Parrish, Andrew; Caswell, Richard; Stals, Karen; Durigon, Romina; Durlacher-Betzer, Karina; Cunningham, Mitch; Grochowski, Christopher M.; Baptista, Júlia; Tysoe, Carolyn; Baple, Emma L.; Lahiri, Nayana; Homfray, Tessa; Scurr, Ingrid; Armstrong, Catherine; Dean, John; Pelayo, Uxoa Fernandez; Jones, Aleck W.E.; Taylor, Robert W.; Misra, Vinod K.; Yoon, Wan Hee; Wright, Caroline F.; Lupski, James R.; Spinazzola, Antonella; Harel, Tamar; Holt, Ian; Ellard, Sian

doi:10.1016/j.ajhg.2020.01.007

Cited by 39 publications

(51 citation statements)

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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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Section: Introductionmentioning

confidence: 99%

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

et al. 2021

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“…Indeed, the knockdown of ATAD3 has been associated with a reduction in mtDNA content [ 170 ]. In human fibroblasts that are either deficient for ATAD3 or harbour a duplication of the ATAD3 gene cluster, nucleoids were found to be enlarged and clustered together suggesting a role of ATAD3 and fusion in mtDNA distribution [ 171 , 172 ]. The knockout of ATAD3 in skeletal muscle has been associated with the progressive formation of mtDNA deletions and copy number depletion [ 173 ].…”

Section: Membrane Dynamics and The Organisation Of Mtdnamentioning

confidence: 99%

The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes

Chapman

Nicholls

2020

Life

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Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure.

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“…Affected individuals whose fibroblasts exhibited impaired cholesterol metabolism often presented with elevated urine levels of 3-methyglutaconic acid (3-MGA). 10,12,15 Interestingly, reading of this manuscript. We appreciate Dr. Sheng Zhang's kind gift of rabbit anti-Ref2(P)…”

Section: Drosophila Studies Of Missense Variantsmentioning

confidence: 99%

“…12 The reciprocal, NAHR-mediated duplication at this locus, between ATAD3C and ATAD3A, results in a fusion gene encoding a dysfunctional protein. 15 Homozygosity for presumed hypomorphic missense alleles (p.Thr53Ile, p.Thr84Met) leads to bilateral cataracts, hypotonia, ataxia and cerebellar atrophy. 10; 16 Finally, a recurrent de novo heterozygous missense variant (p.Arg528Trp) acts as an antimorph or dominant-negative allele and gives rise to a phenotypic spectrum including developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Functional interpretation ofATAD3Avariants in neuro-mitochondrial phenotypes

Yap

Park

Wortmann

et al. 2020

Preprint

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BackgroundThe 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.ObjectiveTo expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles.MethodsExome sequencing was used to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3A Gal4 trap null allele was generated using CRISPR-Cas9 genome editing technology to aid interpretation of variants.ResultsWe report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. Four of the identified missense variants, p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val), were inherited in trans to loss-of-function alleles. A fifth missense variant, p.(Arg327Pro), was homozygous. 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, and Arg327Pro are severe loss-of-function alleles leading to early developmental lethality and neurogenesis defects, whereas Leu77Val and Arg170Trp are partial loss of function alleles that cause progressive locomotion defects. Moreover, Leu77Val and Arg170Trp expression leads to an increase in autophagy and mitophagy in adult muscles.ConclusionOur 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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Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism

Cited by 39 publications

References 22 publications

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes

Functional interpretation ofATAD3Avariants in neuro-mitochondrial phenotypes

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