A fourth mutation, ames waltzer, for deafness and circling behavior, also on mouse Chromosome 10, has been genetically mapped. We have cloned the region around that gene and are determining if any genes are different in this mutant. In collaboration with Richard Altschuler, David Dolan and Yehoash Raphael (U-M Kresge Hearing Research Institute) we are characterizing the defect in this mutant.
In collaboration with Daniel Goldman (MHRI), Mark Hankin (Medical College of Toledo) and Roderick McInnes (Hospital for Sick Children, Toronto) we have used the same strategy to determine the genetic defect of the mouse mutation, ocular retardation, which affects early neural- retina development and causes extremely small eyes (microphthalmia). We have identified the ocular retardation mutation in the gene for <Chx10>, a likely transcription factor. Mutations in this gene may also lead to microphthalmia in humans. In addition, we have found that other genes ("modifier genes") interact with this mutation, and gene mapping strategies have been employed to identify three distinct regions of the genome where such modifier genes are located. Mapping these genes will not only help to elucidate the complex phenotype of the ocular retardation mutation but will also be used as a model for the genetic analysis of complex gene-gene interactions that are likely to play a role in behavioral and psychiatric disorders. A second allele, <or2J>, which in addition is sterile, was shown to be a large (>75 kb) deletion which is postulated to lead to the deletion of a second gene responsible for the sterility.
We are in the process of cloning the gene involved in a novel mouse mutant, caused by insertion of a transgene, which was discovered to be exceptionally aggressive. Standardized tests have shown that males are significantly more aggressive and that the aggressiveness co-segregates with the transgene. Cloning of the sites where the transgene is inserted is in progress and is expected to allow us to identify a novel gene involved in aggressive behavior.
Kantheti P, Qiao X, Diaz M, Peden AA, Meyer GE, Carskadon SL, Kapfhamer D, Sufalko D, Robinson MS, Noebels NL, Burmeister M: Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 21:111-122, 1998.
Zobeley E, Sufalko DS, Adkins S, Burmeister M: Fine genetic and comparative mapping of the deafness mutation Ames waltzer on mouse Chromosome 10. Genomics 50:260-266, 1998.
Bespalova IN, Adkins S, Burmeister M: 3' RACE: Skewed Ratio of Specific to General PCR Primers Improves Yield and Specificity. Biotechniques 24: 575-577, 1998.
Bespalova IN, Adkins SA, Pranzatelli M, Burmeister M: Novel Cystatin B mutation and Novel cystatin B mutation and diagnostic PCR assay in an Unverricht-Lundborg Progressive Myoclonus epilepsy patient. Amer J Med Genet (Neuropsych Genet) 74(5):467-471, 1997.
Burmeister, M., Novak, J., Liang, M.-Y., Basu, S., Ploder, L., Hawes, N.L., Vidgen, D., Hoover, F., Goldman, D., Kalnins, V.I., Roderick, T.H., Taylor, B.A., Hankin, M.H. and McInnes, R.R.: Ocular retardation mouse caused by <Chx10> homeobox null allele: Impaired retinal progenitor proliferation and bipolar cell differention. Nature Genet 42(4):376-384 (1996). This article is also discussed in "News and Views" in the same issue.
Kapfhamer, D., Sweet, H.O., Sufalko, D., Warren, S., Johnson, K.R. and Burmeister, M.: The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse Chromosome 10 homologous to 19p13.3. Genomics 35:533-538 (1996).