Lethargic 4 Jackson; a new spontaneous mutation in the Cacnb4 gene

Son Yong Karst, Sandra Gray, Patricia F. Ward-Bailey, Leah Rae Donahue, Kenneth R. Johnson, Muriel T. Davisson

Source of Support: The 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:Cacnb4^lh-4J

Mutation (allele) name: lethargic 4 Jackson

Gene symbol: Cacnb4

Strain of origin: C3Fe.SWV-Mbp^shi/J

Current strain name: C3Fe(SWV)-Cacnb4^lh-4J/J

Stock #:007499 (view JAX® Mice Data Sheet for additional information including Price and Supply Information) NOTE: After 4-24-2008 available as DNA only from the Jackson Laboratory DNA Resource.

Phenotype categories: neurological/ behavioral: motor capabilities/coordination/movement

Abstract

The new recessive lethargic 4 Jackson mutation arose spontaneously and has been identified as a remutation of the Cacnb4gene by its map position on Chromosome 2 and by a direct test for allelism.

Origin and Description

The lethargic 4 Jackson remutation arose in a production colony of C3Fe.SWV-Mbp^shi/J mice at the Jackson Laboratory in 2001 and was discovered by Cheryl Crabtree. Mice homozygous for the new lethargic 4 Jackson remutation exhibit the wobbly gait behavior and smaller body size that is characteristic of the original lethargic mutation (Cacnb4^1h), however seizures have not been reported in this new remutation. Females breed but males have not bred to date. Both sexes live a normal lifespan.

Genetic Analysis

Using our standard mapping procedures C3Fe(SWV)-Cacnb4^lh-4J/J mice were mated to CAST mice. The progeny produced by that mating were then intercrossed and they produced 50 F2 mutant mice that were utilized for linkage analysis.

The Cacnb4^lh mutation maps to Chromosome 2 between D2Mit7 (NCBIm 36 position 38.06 Mb) and D2Mit61 (NCBIm 36 position 60.49 Mb) and is non-recombinant with D2Mit157 (NCBIm 36 position 55.6 Mb). The original Cacnb4^lh/J mutation is located at (NCBIm 36) position 52.2-52.4 Mb.

A direct test for allelism was set up by mating a heterogous female B6EiC3Sna/A-Cacnb4^lh/J (Stock#000504) mouse with a heterozygous male C3Fe(SWV)-Cacnb4^lh-4J/J mouse. This mating produced 38 progeny of which 10 expressed the mutant phenotype, proving allelism.

Pathology

A pathological screen of one female homozygote at 9 months of age showed no lesions and the myelin looked normal. One homozygous male at 32 weeks age had fewer than normal granule cells at base of folia and no other lesions. Another homozygous male at 32 weeks of age showed mild hydrocephalus and possibly Purkinje cell dendrites.

Hearing as accessed by auditory brainstem response testing(ABR) of mutant mice was normal.

The eyes of mutant mice were examined with an opthalamascope and displayed retinal degeneration which is clinically normal for the C3H mouse strains, the predominant inbred background in the C3Fe(SWV)-Cacnb4^lh-4J/J strain, and not caused by the lh-4J mutation.

Acknowledgements

The authors wish to thank Cheryl Crabtree for discovery of the mutant, Chantal Longo-Guess for hearing assessment, Norm Hawes and Ron Hurd for the eye examinations, and Coleen Marden for excellent pathological skills.

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