Incidental Mutation 'N/A:Chchd4'

• ID: 43
• Institutional Source: Beutler Lab
• Gene Symbol: Chchd4
• Ensembl Gene: ENSMUSG00000034203
• Gene Name: coiled-coil-helix-coiled-coil-helix domain containing 4
• Synonyms: 2810014D17Rik, 2410012P20Rik
• Essential gene?: Probably essential (E-score: 0.933)
• Stock #: N/A of strain 294
• Status: Validated
• Chromosome: 6
• Chromosomal Location: 91441258-91450405 bp(-) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): T to C at 91442187 bp (GRCm39)
• Zygosity: Homozygous
• Amino Acid Change: Tyrosine to Cysteine at position 77 (Y77C)
• Ref Sequence: ENSEMBL: ENSMUSP00000041380
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000040835]
• AlphaFold: Q8VEA4
• Predicted Effect: probably damaging; Transcript: ENSMUST00000040835; AA Change: Y77C; PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
• SMART Domains: Protein: ENSMUSP00000041380; Gene: ENSMUSG00000034203; AA Change: Y77C

Domain	Start	End	E-Value	Type
Pfam:CHCH	64	100	8.4e-12	PFAM
low complexity region	109	123	N/A	INTRINSIC

• Meta Mutation Damage Score: 0.4685
• Coding Region Coverage:
  • 1x: 88.7%
  • 3x: 76.0%
• Validation Efficiency: 91% (106/116)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] CHCHD4, a component of human mitochondria, belongs to a protein family whose members share 6 highly conserved cysteine residues constituting a -CXC-CX(9)C-CX(9)C- motif in the C terminus (Hofmann et al., 2005 [PubMed 16185709]).[supplied by OMIM, Mar 2008]
• Allele List at MGI:

  All alleles(21) : Gene trapped(21)

• Posted On: 2009-11-09

Nature of Mutation

DNA sequencing using the SOLiD technique identified a T to C transition at position 316 of the Chchd4 transcript, in exon 3 of 3 total exons. The mutated nucleotide causes a tyrosine to cysteine substitution at amino acid 77. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

 

Protein Function and Prediction

The Chchd4 gene encodes a 139 amino acid protein (MIA40) that is a mitochondrial intermembrane space (IMS) import and assembly protein (Uniprot Q8VEA4). This protein is required for the import and assembly of small cysteine-containing proteins in the IMS.  Precursor proteins to be imported into the IMS are translocated in their reduced form into the mitochondria. The oxidized form of MIA40 forms a transient intermolecular disulfide bridge with the reduced precursor protein, resulting in oxidation of the precursor protein. The precursor protein now contains an intramolecular disulfide bond and is able to undergo folding in the IMS. MIA40 contains a CHCH domain (amino acids 57-100), which consists of a conserved twin Cys-X(9)-Cys motif required for import and stability of MIA40 in mitochondria.  The Y77C mutation is located in the CHCH domain, and is predicted to be probably damaging by the PolyPhen program.