ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia

De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominant...

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Vydané v:	Human molecular genetics Ročník 26; číslo 8; s. 1432 - 1443
Hlavní autori:	Cooper, Helen M, Yang, Yang, Ylikallio, Emil, Khairullin, Rafil, Woldegebriel, Rosa, Lin, Kai-Lan, Euro, Liliya, Palin, Eino, Wolf, Alexander, Trokovic, Ras, Isohanni, Pirjo, Kaakkola, Seppo, Auranen, Mari, Lönnqvist, Tuula, Wanrooij, Sjoerd, Tyynismaa, Henna
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England 15.04.2017
Predmet:	Adenosine Triphosphatases - biosynthesis Adenosine Triphosphatases - genetics Adolescent Adult ATPases Associated with Diverse Cellular Activities Axons - metabolism Axons - pathology Cerebral Palsy - genetics Cerebral Palsy - pathology Child, Preschool Female Gene Expression Regulation Humans Male Membrane Proteins - biosynthesis Membrane Proteins - genetics Mitochondria - metabolism Mitochondria - pathology Mitochondrial Dynamics - genetics Mitochondrial Membranes - metabolism Mitochondrial Membranes - pathology Mitochondrial Proteins - biosynthesis Mitochondrial Proteins - genetics Mutation Spastic Paraplegia, Hereditary - genetics Spastic Paraplegia, Hereditary - pathology TOR Serine-Threonine Kinases - genetics
ISSN:	1460-2083
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Shrnutí:	De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1460-2083
DOI:	10.1093/hmg/ddx042