Phenotypic Mutation 'gizmo'

• Allele: gizmo
• Chromosome: 13
• Gene: Edaradd
• Gene Name: EDAR associated via death domain
• Synonym(s): EDAR (ectodysplasin-A receptor)-associated death domain, 1810032E07Rik, 5830469M23Rik
• Chromosomal Location: 12,487,513-12,535,319 bp (-) (GRCm39)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene was identified by its association with ectodermal dysplasia, a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands. The protein encoded by this gene is a death domain-containing protein, and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth and other ectodermal derivatives. This protein and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth. Through its interaction with EDAR, this protein acts as an adaptor, and links the receptor to downstream signaling pathways. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008] ; PHENOTYPE: Spontaneous mutations may lead to a kinked tail, reduced fertility, abnormal respiration and sparse hair. Chemically-induced mutants may show developmental defects in teeth, hair and ectoderm-derived glands, reduced viability and fertility, respiratory disorders, and lipid, myelin and brain defects. [provided by MGI curators]
• Mapped: Yes
• Institutional Source: Beutler Lab
• Ref Sequences:
  Ensembl: ENSMUSP00000039292
  Ensembl: ENSMUSP00000136158
• Gene Model: not available
• AlphaFold: no structure available at present
• Meta Mutation Damage Score: Not available
• Is this an essential gene?: Possibly essential (E-score: 0.685)
• Phenotypic Category: Autosomal Recessive
• Penetrance: 100%
• Mode of Inheritance: Autosomal Recessive
• Local Stock: Embryos, Sperm, gDNA
• Last Updated: 2016-05-13 3:09 PM by Diantha La Vine
• Record Created: unknown
• Record Posted: 2008-02-08
• Science Writers: Eva Marie Y. Moresco
• Illustrators: Diantha La Vine
• Authors: Xin Du, Christina Gil-Lamagniere, Bruce Beutler

Accession Number

NCBI RefSeq: NM_133643; MGI: 1931001

Alleles Listed at MGI

All alleles(7) : Gene trapped(2) Spontaneous(2) Chemically induced(3)

Repository

none

Phenotypic Description

The gizmo phenotype was identified among G3 ENU-mutagenized mice.  Homozygous gizmo mutants are very small and thin, have poor coat quality, and have large ears that lack hair around the base.  The mice occasionally make a chirping noise when breathing, consistent with an airway anomaly.  The animals resemble achtung, achtung2 or tabby/Sleek/downless/crinkled mice, which have mutations in components of the EDAR signaling pathway (1-5). Gizmo is allelic to achtung.

Nature of Mutation

The Edaradd gene from gizmo mutants was sequenced at the cDNA level and found to be lacking the 59-nucleotide exon 4 (out of 6 total exons).  The nature of the mutation at the genomic DNA level has not been determined.  Deletion of exon 4 is predicted to destroy the reading frame of the 208-residue protein following amino acid 43, add four aberrant amino acids, and create a premature stop codon that would truncate the protein after amino acid 47.  Edaradd is located on Chromosome 13.

 

                 <-- exon 3                exon5 -->

13510 GACACCGGCCTCCCTAAAG…exon 4 missing…GGAGAAGAAAATGA 36818

38    -D--T--G--L--P--K--                G--R--R--K--*  47      

              correct                         aberrant

Protein Prediction

Figure 1. Domain structure of EDARADD. The death domain (DD) is predicted to have a predominantly helical secondary structure. The TRAF-binding consensus sequence PIQDT  is indicated. The gizmo mutation results in the addition of four aberrant amino acids, followed by a premature stop condon. This image is interactive. Click on the image to view other mutations found in EDARADD (red). Click on the mutations for more specific information.   

The gizmo mutation is predicted to result in a severely truncated EDARADD protein with four aberrant amino acids added to the C terminus before a premature stop (Figure 1).  The drastic shortening of the protein is likely to destabilize the protein and lead to its degradation, but this has not been tested.

 

Please see the record for achtung for information about Edaradd.

Putative Mechanism

No structural data are currently available for EDARADD.  Other than the putative TRAF-binding consensus sequence located in residues 35-39, no homology to known protein domains has been reported for the N-terminal region of EDARADD.  Because the mutation truncates the protein so severely, gizmo is probably a null allele that abrogates all signaling from EDAR and causes the characteristic hair and gland phenotypes of EDA signaling mutants.  The precise mechanisms by which the EDA pathway regulates development of ectoderm-derived tissues are yet incompletely understood.

Primers

Primers cannot be located by automatic search.

References

   1.  Headon, D. J., Emmal, S. A., Ferguson, B. M., Tucker, A. S., Justice, M. J., Sharpe, P. T., Zonana, J., and Overbeek, P. A. (2001) Gene defect in ectodermal dysplasia implicates a death domain adapter in development, Nature 414, 913-916.

   2.  Yan, M., Zhang, Z., Brady, J. R., Schilbach, S., Fairbrother, W. J., and Dixit, V. M. (2002) Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice, Curr. Biol. 12, 409-413.

   3.  Srivastava, A. K., Pispa, J., Hartung, A. J., Du, Y., Ezer, S., Jenks, T., Shimada, T., Pekkanen, M., Mikkola, M. L., Ko, M. S., Thesleff, I., Kere, J., and Schlessinger, D. (1997) The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains, Proc. Natl. Acad. Sci. U. S. A 94, 13069-13074.

   4.  Ferguson, B. M., Brockdorff, N., Formstone, E., Ngyuen, T., Kronmiller, J. E., and Zonana, J. (1997) Cloning of Tabby, the murine homolog of the human EDA gene: evidence for a membrane-associated protein with a short collagenous domain, Hum. Mol. Genet. 6, 1589-1594.

   5.  Headon, D. J. and Overbeek, P. A. (1999) Involvement of a novel Tnf receptor homologue in hair follicle induction, Nat. Genet. 22, 370-374.