Incidental Mutation 'F2404:Epha3'

• ID: 170
• Institutional Source: Beutler Lab
• Gene Symbol: Epha3
• Ensembl Gene: ENSMUSG00000052504
• Gene Name: Eph receptor A3
• Synonyms: End3, Tyro4, Cek4, Hek, Hek4, Mek4
• Essential gene?: Possibly non essential (E-score: 0.273)
• Stock #: F2404 of strain feckless
• Status: Validated
• Chromosome: 16
• Chromosomal Location: 63363897-63684538 bp(-) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): A to G at 63366531 bp (GRCm39)
• Zygosity: Heterozygous
• Amino Acid Change: Leucine to Proline at position 972 (L972P)
• Ref Sequence: ENSEMBL: ENSMUSP00000155946
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000064405] [ENSMUST00000232049]
• AlphaFold: no structure available at present
• Predicted Effect: probably benign; Transcript: ENSMUST00000064405; AA Change: L973P; PolyPhen 2 Score 0.008 (Sensitivity: 0.96; Specificity: 0.76)
• SMART Domains: Protein: ENSMUSP00000066554; Gene: ENSMUSG00000052504; AA Change: L973P

Domain	Start	End	E-Value	Type
signal peptide	1	20	N/A	INTRINSIC
EPH_lbd	29	202	1.76e-127	SMART
Pfam:GCC2_GCC3	263	306	6.6e-9	PFAM
FN3	326	418	1.14e-5	SMART
FN3	437	518	4.8e-13	SMART
Pfam:EphA2_TM	543	619	8.2e-25	PFAM
TyrKc	622	879	5.16e-140	SMART
SAM	909	976	1.08e-13	SMART

• Predicted Effect: probably benign; Transcript: ENSMUST00000232049; AA Change: L972P; PolyPhen 2 Score 0.136 (Sensitivity: 0.92; Specificity: 0.86)
• Meta Mutation Damage Score: 0.1660
• Coding Region Coverage:
  • 1x: 87.2%
  • 3x: 68.2%
• Validation Efficiency: 89% (81/91)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008] ; PHENOTYPE: Mice homozygous for disruptions in this gene usually die within 48 hours of birth of cardiac failure. Survivors develop normally with no indications of cardiac abnormalities. [provided by MGI curators]
• Allele List at MGI:

  All alleles(3) : Targeted, knock-out(1) Gene trapped(2)

• Posted On: 2010-04-12

Nature of Mutation

DNA sequencing using the SOLiD technique identified a T to C transition at position 3028 of the Epha3 transcript in exon 17 of 17 total exons. The mutated nucleotide causes a leucine to proline substitution at amino acid 973 of the encoded protein. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Epha3 gene encodes the 984 amino acid ephrin type-A receptor 3 (EPHA3). EPHA3 is a receptor for ephrin-A ligands. It is a single-pass type I membrane protein with a tyrosine kinase cytoplasmic domain, and is expressed predominantly in the brain and testis. The extracellular region of EPHA3 contains two fibronectin type III domains. The cytoplasmic region contains one sterile alpha motif (SAM) domain and a PDZ-binding motif at the C-terminus, both of which are protein interaction motifs (Uniprot P29319). Mice homozygous for disruptions in this gene usually die within 48 hours of birth of cardiac failure. Survivors develop normally with no indications of cardiac abnormalities.

 

The L973P change occurs in the SAM domain, and is predicted to be probably damaging by the PolyPhen program.