International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 217 - AMYLOID PRECURSOR PROTEIN (APP) LEVELS MAY AFFECT PENETRANCE OF THE SEMI-DOMINANT PHENOTYPES THAT ARE PRODUCED BY A NEW ENU-INDUCED MUTANT ALLELE, higher stepper (Hst) OF THE VOLTAGE DEPENDENT CALCIUM CHANNEL GENE cacna1a

Mr George A Carlson
McLaughlin Research Institute
1520 Twenty-Third Street South
Great Falls
Montana
59405
USA

Co-Authors:  Gilchrist J, Peterson D, Stephenson DA, and Toxopeus C 
Institution:   McLaughlin Research Institute  

Amyloid precursor protein (app) levels may affect penetrance of the semi-dominant phenotypes that are produced by a new enu-induced mutant allele of the voltage dependent calcium channel gene cacna1a

Amyloid plaques in the brains of Alzheimer’s disease (AD) patients are composed of Aß peptide cleavage products of APP. Although APP is intimately involved in AD, its physiological functions are unknown.  A sensitized screen for ENU-induced mutations in genes relevant to APP function was undertaken.

Offspring of ENU-treated C57BL/6J (B6) males and FVB/N (FVB) were screened at weaning and again two weeks later using simple battery of neurological and behavioral tests. A (FVBxB6)G1 female with a subtle highstepping gait was detected in the second screen and was mated to FVB/N and FVB.129-App-null mice to test heritability.  Twenty-six of 69 offspring presented around the time of weaning with phenotypes not seen in the founder.  The affected mice exhibited poor coordination and exaggerated, slow movements.  This severe phenotype disappeared within 3 days of weaning and only a mild gait abnormality persisted. The mutation, designated Highstepper or Hst, was mapped to a region of Chromosome 8 in the vicinity of Cacna1a.  Allelism tests with B6.D2-Cacna1atg tottering mice indicated that Hst is a new mutant allele of Cacna1a. 

Results from genotyped Cacna1aHst carriers suggested an effect of App on penetrance Only 36 of 58 (62%) Hst carriers homozygous for wildtype App were affected, while 43 of 57 (75%) carriers with one App null allele were affected.  In contrast, all 17 App null homozygous Hst carriers exhibited the phenotype.  There also is at least one modifier gene differing between B6 and FVB that alters penetrance of Cacna1aHst.


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