Abstract
ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 831-845 |
| Number of pages | 15 |
| Journal | American Journal of Human Genetics |
| Volume | 99 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Oct 6 2016 |
Fingerprint
Keywords
- ATAD3A
- cardiomyopathy
- CNV
- de novo variant
- dominant negative
- mitochondrial dynamics
- neuropathy
- optic atrophy
- whole-exome sequencing
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. / Harel, Tamar; Yoon, Wan Hee; Garone, Caterina; Gu, Shen; Coban-Akdemir, Zeynep; Eldomery, Mohammad K.; Posey, Jennifer E.; Jhangiani, Shalini N.; Rosenfeld, Jill A.; Cho, Megan T.; Fox, Stephanie; Withers, Marjorie; Brooks, Stephanie M.; Chiang, Theodore; Duraine, Lita; Erdin, Serkan; Yuan, Bo; Shao, Yunru; Moussallem, Elie; Lamperti, Costanza; Donati, Maria A.; Smith, Joshua D.; McLaughlin, Heather M.; Eng, Christine M.; Walkiewicz, Magdalena; Xia, Fan; Pippucci, Tommaso; Magini, Pamela; Seri, Marco; Zeviani, Massimo; Hirano, Michio; Hunter, Jill V.; Srour, Myriam; Zanigni, Stefano; Lewis, Richard Alan; Muzny, Donna M.; Lotze, Timothy E.; Boerwinkle, Eric; Gibbs, Richard A.; Hickey, Scott E.; Graham, Brett H.; Yang, Yaping; Buhas, Daniela; Martin, Donna M.; Potocki, Lorraine; Graziano, Claudio; Bellen, Hugo J.; Lupski, James R.
In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 831-845.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes
AU - Harel, Tamar
AU - Yoon, Wan Hee
AU - Garone, Caterina
AU - Gu, Shen
AU - Coban-Akdemir, Zeynep
AU - Eldomery, Mohammad K.
AU - Posey, Jennifer E.
AU - Jhangiani, Shalini N.
AU - Rosenfeld, Jill A.
AU - Cho, Megan T.
AU - Fox, Stephanie
AU - Withers, Marjorie
AU - Brooks, Stephanie M.
AU - Chiang, Theodore
AU - Duraine, Lita
AU - Erdin, Serkan
AU - Yuan, Bo
AU - Shao, Yunru
AU - Moussallem, Elie
AU - Lamperti, Costanza
AU - Donati, Maria A.
AU - Smith, Joshua D.
AU - McLaughlin, Heather M.
AU - Eng, Christine M.
AU - Walkiewicz, Magdalena
AU - Xia, Fan
AU - Pippucci, Tommaso
AU - Magini, Pamela
AU - Seri, Marco
AU - Zeviani, Massimo
AU - Hirano, Michio
AU - Hunter, Jill V.
AU - Srour, Myriam
AU - Zanigni, Stefano
AU - Lewis, Richard Alan
AU - Muzny, Donna M.
AU - Lotze, Timothy E.
AU - Boerwinkle, Eric
AU - Gibbs, Richard A.
AU - Hickey, Scott E.
AU - Graham, Brett H.
AU - Yang, Yaping
AU - Buhas, Daniela
AU - Martin, Donna M.
AU - Potocki, Lorraine
AU - Graziano, Claudio
AU - Bellen, Hugo J.
AU - Lupski, James R.
PY - 2016/10/6
Y1 - 2016/10/6
N2 - ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
AB - ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
KW - ATAD3A
KW - cardiomyopathy
KW - CNV
KW - de novo variant
KW - dominant negative
KW - mitochondrial dynamics
KW - neuropathy
KW - optic atrophy
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=84991678519&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84991678519&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2016.08.007
DO - 10.1016/j.ajhg.2016.08.007
M3 - Article
AN - SCOPUS:84991678519
VL - 99
SP - 831
EP - 845
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -