A new X-linked dominant mutation called wavy tiger

Jill Giggey, Leona Gagnon, Eva Eicher, Belinda Harris, and Leah Rae Donahue

 

Source of Support: This research is supported by a grant awarded to The Jackson

Laboratory by The National Eye Institute titled "Gene Discovery For Craniofacial

Disorders" (ROI 010173- Dr. Leah Rae Donahue, PI) and Mouse Mutant Resource (RR

01183-Dr. Muriel Davisson, PI).

Mutation (allele) symbol: Wtgr

Mutation (allele) name: wavy tiger

Gene symbol: Wtgr

Strain of origin: D2(B6)/Ei

Current strain name: D2(B6)-Wtgr/EiGrsrJ

Stock #: 003397 (view JAX® Mice Data Sheet for additional information including Price and Supply Information)

Phenotypic categories: skin and hair

Origin and Description

 

We report here a new dominant X-linked mutation that was discovered in a research colony by Eva Eicher at The Jackson Laboratory in 1998. The female mutants (Wtgr/+) are characterized by a small size, a wavy coat that appears striped, and curly whiskers (See Photo). Because of their small size, the litters are weaned at a later age, usually around 4-5 weeks. The stock is maintained by mating a heterozygous (Wtgr/+) mutant female to a control (+/y) male. Hemizygous (Wtgr/Y) mutant males on the D2(B6) background rarely survive to adulthood but do not reproduce. Examination of sperm reveals lack of motility of most sperm with occasional motility for short periods of time. Hemizygous mutant males (Wtgr/Y) are viable on the CAST/Ei and C57BL/6J hybrid backgrounds. Heterozygous mutant females (Wtgr/+) are fertile but have small litters. Hearing was assessed by auditory brain stem response (ABR). Female control (+/+) and heterozygous mutant (Wtgr/+) mice have normal hearing at three weeks of age. However, the mice develop age-related hearing loss due to the DBA background strain. The hearing of mutant and control mice is  normal on a D2(B6) X B6 F1 hybrid mixed background at all ages assessed. The Wtgr mutation was mapped to Chromosome X between the markers DXMit62 (89.07 Mb NCBIm36) and DXMit16 (95.5 Mb) distal to the striated (Str),and bare patches (Bpa) gene and proximal to tabby (Ta). Because of the wavy coat that causes striping on the fur, we named this mutation Wavy tiger.

Genetic Analysis

For linkage analysis, a normal CAST/Ei male was mated to a heterozygous mutant female (Wtgr/+). Visible heterozygous female mutants (Wtgr/+) from the F1 generation were then backcrossed to an unrelated D2(B6) control (+/Y) male. Spleens of affected hemizygous mutant males (Wtgr/y) and unaffected control males were collected and stored at -70° C for subsequent DNA typing to map the location. DNA was extracted from thirty-nine controls (+/Y) and twenty-four hemizygous male mutants (Wtgr/Y) and polymerase chain reaction was carried out with MIT primer pairs (MapPairs, Research Genetics, Huntsville Ala.) Initial genetic mapping along the X chromosome using mutant (Wtgr/Y) and control (+/Y) males localized the mutation between 90.9 and 129.1 Mb (Ensembl m36, 2006). This region excluded the candidate gene NAD(P) dependent steroid dehydrogenase-like (Nsdhl), the gene responsible for Bpa and Str mutations, but includes ectodysplasin-A (Eda) the gene underlying the (Ta) mouse mutation. Further analysis utilizing the female backcross progeny refines the distal flanking marker at DXMit16 (95.5 Mb), thus excluding Eda as a candidate gene. A candidate gene within this region is ectodysplasin A2 isoform receptor (Eda2r) because mutations of this gene cause hypohidrotic ectodermal dysplasia (Newton, 2004).

Pathology

A standard pathological screen of one heterozygous female mutant at eleven weeks of age and two heterozygous female mutants at 4 weeks of age showed that clumps of melanocytes are present in the dermis and in the subdermal adipose tissue (Figure 1). This is never seen in normal mice. The zigzag hairs are abnormally thin, slightly wavy, and have clumps of melanin (Fig. 2 and 3).

Acknowledgements

The authors would like to thank Lisa Somes for maintaining the colony, Norm Hawes for examination of the eyes, Heping Yu for hearing assessment, Rod Bronson and Coleen Marden for pathological evaluation and Pat Ward-Bailey for manuscript preparation assistance.

References

Mouse Genome Database (MGD) Mouse Genome Informatics Project, The Jackson

Laboratory, Bar Harbor, Maine. World Wide Web (URL: http://www.informatics.jax.org).

Newton K, French DM, Yan M, Frantz GD and Dixit VM (2004). Myodegeneration in EDA-A2 transgenic mice is prevented by XEDAR deficiency. Mol Cell Biol, 24(4): 1608-13.

Zheng QY, Johnson KR, Erway LC (1999). Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 130, 94-107.