Flying Squirrel; a new neurological mutation on Chromosome 10.

Authors: Son Yong Karst, Patricia F. Ward-Bailey, Richard Samples, Kenneth R. Johnson, Leah Rae Donahue and Muriel T. Davisson

Source of Support:This research was supported by NIH/NCRR grant RR01183 to the Mouse Mutant Resource (M.T. Davisson, PI) and Cancer Center Core Grant CA34196.

Mutation (allele) symbol: fsq

Mutation (allele) name: flying squirrel

Gene symbol: fsq

Strain of origin: KK.Cg-Ay/J

Current strain name: KK(Cg)-fsq/J

Stock #:008296 (view JAX® Mice Data Sheet for additional information including Price and Supply Information)

Phenotype categories: Neurological

 

Origin and Description

Mice affected by the new flying squirrel (fsq) mutation were discovered by Arcel Dullas in a production colony of KK.Cg-Ay/J mice at The Jackson Laboratory. Because this new mutant strain was difficult to maintain, in vitro fertilization was performed with sperm from a mutant male  into  KK/Cg-A<y>J donor females. The presumed heterozygous progeny from this fertilization were then mated together and generated mutant progeny to maintain the flying squirrel (fsq) colony.

The heteroygote mice that were produced from this mating had two genotypes and phenotypes: Ay/a fsq/+ (yellow coat color) and a/a fsq/+(black coat color). The flying squirrel colony was generated using only a/a fsq/+ black coat color mice.

Flying squirrel (fsq) mutant mice can be recognized at about 2 months of age when their bodies become stiff overall, in both limbs and trunk, but especially on the ventral side of the body. They take on a rigid spread out posture when picked up and sometimes will clasp their legs inward. Flying squirrel (fsq) mutant mice walk with a slight stagger and older homozygous mutant mice can't right themselves and their entire body seems rigid. Homozygous flying squirrel (fsq) mice can live to adulthood and are not fertile. Heterozygotes also have a normal lifespan but do breed.

Genetic Analysis

This new mutation has recessive inheritance as shown by mating a homozygous fsq/fsq mouse to an unrelated male CAST/EiJ mouse. This mating produced unaffected F1 progeny proving the new mutation to be recessive. The unaffected F1 hybrids were intercrossed, and 43 affected F2 animals were generated for linkage analysis. Using our standard mapping protocols this new mutation was mapped to Chromosome 10, between D10Mit54 (NCBI 36 position 43.3 Mb) and D10Mit138 (NCBI 36 position 53.4 Mb) and is non- recombinant with D10Mit89, D10Mit256 and D10Mit218 (84 meioses tested). A search in Mouse Genome Informatics (MGI) for known genes causing neuromuscular phenotypes, that are located between our flanking markers, yielded none. Another search for genes with neurological phenotypes, located in our region of interest produced four genes, all of which had very different phenotypes compared to the flying squirrel (fsq) phenotype and therefore not likely candidate genes.

Pathology

Hearing as assessed by auditory brain stem response testing (ABR) of two homozygous mice and one control at 11 weeks of age showed that the homozygous mice were deaf and the control mouse had elevated thresholds. Fourteen non-mutant mice of the KK.Cg-A<y>/J background strain tested at 6-8 weeks of age exhibited hearing impairment (ABR thresholds 20-30 dB above normal) similar to that of the littermate control mouse tested at 11 weeks of age, but not as severe as that of the two mutant mice, which showed no response to 100 dB SPL stimuli when tested at 11 weeks of age.

The eyes of 3 female homozygous mice were examined with am opthalamascope and had suture cataracts plus haze and wavy retinal blood vessels at 2 months of age. Three control males (+/?) had normal lenses. Electroretinogram testing (ERG) of one homozygous mutant had poor cone and poor flicker; one heterozygote had late cone. Fluorescein staining showed homozygous mice had wavy retinal vessels and leakage along the vessel. Ten unaffected mice of the background strain KK.Cg-Ay/J were also tested and most of mice had curly vessels indicating that the wavy vessel phenotype is a background effect and not caused by the fsq mutation.

A routine pathological screen of a homozygous mouse at 16 week of age, showed no muscle lesions; mild hydrocephalus and the ear sections were poor. A homozygous mouse at age of 10 weeks showed mineral in wall of bladder and the other homozygous mouse at age of 10 weeks had a few dystrophic axons in spinal cord; legs had no abnormal muscle. We also screened five homozygous mice at 16 weeks and 21 weeks and one had severe hydrocephalus, another one had moderately severe hydrocephalus and all had no other lesions.

Acknowledgements

We thank Arcel Dullas for discovery of the mutant, Roderick Bronson and Coleen Marden for pathological screening, Chantal Longo-Guess for hearing assessment, Norm Hawes and Ron Hurd for the eye examinations.