Incidental Mutation 'E2594:Atad3a'
ID 3
Institutional Source Beutler Lab
Gene Symbol Atad3a
Ensembl Gene ENSMUSG00000029036
Gene Name ATPase family, AAA domain containing 3A
Synonyms Tob3, 2400004H09Rik
Accession Numbers
Essential gene? Essential (E-score: 1.000) question?
Stock # E2594 of strain daniel_gray
Quality Score
Status Validated
Chromosome 4
Chromosomal Location 155825098-155845550 bp(-) (GRCm39)
Type of Mutation unclassified
DNA Base Change (assembly) G to A at 155835390 bp (GRCm39)
Zygosity Heterozygous
Amino Acid Change
Ref Sequence ENSEMBL: ENSMUSP00000138808 (fasta)
Gene Model predicted gene model for transcript(s): [ENSMUST00000030903] [ENSMUST00000176043] [ENSMUST00000184913]
AlphaFold Q925I1
Predicted Effect probably benign
Transcript: ENSMUST00000030903
SMART Domains Protein: ENSMUSP00000030903
Gene: ENSMUSG00000029036

DomainStartEndE-ValueType
Pfam:DUF3523 26 285 9.5e-113 PFAM
AAA 343 482 4.43e-9 SMART
Predicted Effect noncoding transcript
Transcript: ENSMUST00000126725
Predicted Effect noncoding transcript
Transcript: ENSMUST00000134317
Predicted Effect probably benign
Transcript: ENSMUST00000175679
Predicted Effect probably benign
Transcript: ENSMUST00000176043
SMART Domains Protein: ENSMUSP00000135405
Gene: ENSMUSG00000029036

DomainStartEndE-ValueType
Pfam:DUF3523 20 193 5e-50 PFAM
Predicted Effect noncoding transcript
Transcript: ENSMUST00000176839
Predicted Effect probably benign
Transcript: ENSMUST00000184131
Predicted Effect noncoding transcript
Transcript: ENSMUST00000177066
Predicted Effect probably benign
Transcript: ENSMUST00000184913
SMART Domains Protein: ENSMUSP00000138808
Gene: ENSMUSG00000029036

DomainStartEndE-ValueType
Pfam:DUF3523 1 125 9.9e-43 PFAM
Coding Region Coverage
  • 1x: 80.5%
  • 3x: 47.5%
Validation Efficiency 94% (32/34)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. This gene is a member of the ATPase family AAA-domain containing 3 gene family which, in humans, includes two other paralogs. Naturally occurring mutations in this gene are associated with distinct neurological syndromes including Harel-Yoon syndrome. High-level expression of this gene is associated with poor survival in breast cancer patients. A homozygous knockout of the orthologous gene in mice results in embryonic lethality at day 7.5 due to growth retardation and defective development of the trophoblast lineage. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]
PHENOTYPE: Mice homozygous for a gene trapped allele die around E7.5 exhibiting growth retardation, failure to gastrulate, and impaired development of the trophoblast lineage immediately after implantation. [provided by MGI curators]
Allele List at MGI

All alleles(8) : Targeted, other(2) Gene trapped(6)

Other mutations in this stock
Total: 3 list
GeneRefVarChr/LocMutationPredicted EffectZygosity
Adamts17 A G 7: 66,654,098 (GRCm39) S443G probably damaging Homo
Misp3 G A 8: 84,737,331 (GRCm39) probably benign Het
Rigi C T 4: 40,235,282 (GRCm39) W69* probably null Het
Other mutations in Atad3a
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL01620:Atad3a APN 4 155,830,535 (GRCm39) missense probably damaging 0.98
IGL01982:Atad3a APN 4 155,838,384 (GRCm39) missense possibly damaging 0.94
IGL02059:Atad3a APN 4 155,839,207 (GRCm39) splice site probably benign
IGL02572:Atad3a APN 4 155,838,041 (GRCm39) missense possibly damaging 0.61
IGL03086:Atad3a APN 4 155,833,127 (GRCm39) critical splice donor site probably null
IGL03409:Atad3a APN 4 155,831,807 (GRCm39) missense probably damaging 0.99
FR4976:Atad3a UTSW 4 155,838,396 (GRCm39) missense probably damaging 0.98
PIT4618001:Atad3a UTSW 4 155,834,595 (GRCm39) missense probably benign 0.41
R0233:Atad3a UTSW 4 155,830,524 (GRCm39) missense probably damaging 0.99
R0233:Atad3a UTSW 4 155,830,524 (GRCm39) missense probably damaging 0.99
R0601:Atad3a UTSW 4 155,831,864 (GRCm39) missense probably damaging 1.00
R0799:Atad3a UTSW 4 155,831,927 (GRCm39) missense probably damaging 1.00
R1428:Atad3a UTSW 4 155,840,139 (GRCm39) missense probably damaging 1.00
R1597:Atad3a UTSW 4 155,835,892 (GRCm39) critical splice donor site probably null
R2188:Atad3a UTSW 4 155,835,976 (GRCm39) missense probably damaging 0.99
R4126:Atad3a UTSW 4 155,838,518 (GRCm39) splice site probably benign
R4564:Atad3a UTSW 4 155,831,766 (GRCm39) splice site probably null
R5334:Atad3a UTSW 4 155,840,146 (GRCm39) missense probably damaging 1.00
R6354:Atad3a UTSW 4 155,838,402 (GRCm39) missense possibly damaging 0.58
R6481:Atad3a UTSW 4 155,838,098 (GRCm39) splice site probably null
R7220:Atad3a UTSW 4 155,838,498 (GRCm39) missense probably benign 0.02
R7689:Atad3a UTSW 4 155,840,610 (GRCm39) missense probably damaging 0.98
R7949:Atad3a UTSW 4 155,833,152 (GRCm39) missense possibly damaging 0.53
R8127:Atad3a UTSW 4 155,838,396 (GRCm39) missense probably damaging 0.96
R8783:Atad3a UTSW 4 155,840,152 (GRCm39) missense probably damaging 1.00
R8956:Atad3a UTSW 4 155,838,054 (GRCm39) missense probably damaging 0.96
R9019:Atad3a UTSW 4 155,838,052 (GRCm39) missense possibly damaging 0.91
R9636:Atad3a UTSW 4 155,833,616 (GRCm39) missense possibly damaging 0.95
R9706:Atad3a UTSW 4 155,834,929 (GRCm39) critical splice donor site probably null
Nature of Mutation
DNA sequencing using the SOLiD technique identified a C to T transition at position 10161 in the Genbank genomic region NC_000070 for the Atad3a gene on chromosome 4 (CCCCTACCAGCT -> CCTACCAG). The mutation is located within intron 8, nine nucleotides upstream from the start of exon 9, and may impair the acceptor splice site of intron 8. The mutation may result in skipping of the 57 nucleotide exon 9, removing 19 amino acids, but preserve the reading frame following the deletion.  Atad3a contains 16 exons (Figure 1). Multiple isoforms of Atad3a are displayed in Ensembl.
 
     <--exon 8 <--intron 8 exon 9--> exon 10--> <--exon 16
9649 CCCATCCAG………CCCTACCAG GTCAGCAGG……CCTAGCCTG……AGCTGCTGA  19906
299  -P--I--Q-             -V--S--R-……-P--S--L-……-S--C--*   591      
      correct               deleted         correct 
 
The acceptor splice site of intron 8, which may be impaired by the Atad3a mutation, is indicated in blue lettering; the mutated nucleotide is indicated in red lettering. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 2).
Protein Function and Prediction
The 591 amino acid ATAD3 or TOB3 protein is a member of the large family of ATPases associated with various cellular activities (AAA-ATPases). These proteins are involved in proteolysis, membrane fusion, cell-cycle regulation, DNA replication or intracellular trafficking.  Some of these proteins function as subunits of proteolytic complexes, independent proteases, molecular chaperones, and DNA helicases. The AAA-ATPases belong to the AAA+ superfamily of ring shaped P-loop NTPases, which act via the energy-dependent unfolding of macromolecules. Typically, these proteins assemble into large oligomers (often hexamers) that form a ring-shaped structure with a central pore. These proteins produce a molecular motor that couples ATP binding and hydrolysis to changes in conformational states that act upon a target substrate. The AAA module present in these proteins is responsible for ATP binding and hydrolysis, and contains two classical motifs, Walker A (GX4GKT/S) and Walker B, which is composed of four aliphatic residues followed by two negatively charged residues, typically D and E (1). The AAA module of mouse TOB3 occurs at amino acids 351-474.  A 3D structure of the conserved portion of AAA-ATPases is shown in Figure 3 (NCBI pfam00004). If exon 9 of TOB3 is deleted as predicted, the deletion would occur prior to the ATPase domain.
 

The function of TOB3 is poorly studied, but both human and mouse proteins have been localized to the mitochondria and may be necessary for proper mitochondrial function. These studies have suggested roles in facilitating protein transport from the endoplasmic reticulum to the Golgi apparatus, in apoptosis, and for normal cell division (2;3).

References
Posted On 2009-10-27