Garrett and Colleen presenting on 2.26.09
Garrett Kaas and Colleen Campell will be presenting their research at Student Seminar on Thursday, 2.26.09 at noon. As usual, the seminar will be in 2289 CBRB. Garrett and Colleen have provided the following background info for their talks. See you Thursday.
Background for Garrett Kaas’s talk
Lithium has long been used for over half a century as a first line therapy for bipolar affective disorder (BPD) and has proven effective in its treatment. However, the mechanisms underlying the lithium’s therapeutic action still remain elusive. Shudderer (Shu) is an X-linked dominant mutant of Drosophila that is characterized by sporadically occurring leg jerks and uncoordinated movements. Interestingly, the severity of Shu’s behavioral phenotype is significantly reduced by feeding the adult mutants with lithium (Williamson, 1982). To determine the molecular mechanisms that underly the phenotypes of Shu, gene expression profiles were compared between the mutant and wild type flies using RNA extracted from the head. One of the genes significantly up-regulated in Shu was CanA-14F, encoding a catalytic subunit of the Ca2+-activated protein phosphatase calcineurin. CanA-14F resides in the genomic region 14E-14F, to which the Shu mutation was mapped, implying that the primary defect caused by the Shu mutation is misregulation of CanA-14F. Genes involved in the innate immune response were also upregulated in Shu heads, which is likely to be a direct consequence of CanA-14F upregulation, because the innate immune response is known to be mediated by calcineurin activity. In addition, I found that CanA-14F is expressed in both the larval and adult brain and is localized to regions in the CNS containing neuronal cell bodies. Lastly, I was able to rescue the many behavioral and morphological phenotypes of the mutant by overexpressing sarah (sra), an endogenous inhibitor protein of calcineurin activity. These data suggest the major cause of the Shu mutant phenotypes stems from increased calcineurin activity due to increased CanA-14F expression.
Background for Colleen Campbell’s talk
Mapping of a novel Ménière’s disease locus to chromosome 1q32.1-q32.3
C.A. Campbell1,2, J. Webster3, C. Li4, D.A. Stephan3, R.J.H. Smith1,2. 1) Otolaryngology, University of Iowa, Iowa City, IA; 2) Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, IA; 3) Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ; 4) Dept of Biostatistics, Harvard School of Public Health, Boston, MA.
Ménière’s disease (MD; OMIM; Wikipedia) is a complex disorder of unknown etiology characterized by vertigo, sensorineural hearing loss and tinnitus. Its reported incidence in Caucasians is 1-2 per 10,000 (Morrison 1995), but most cases of MD are sporadic and only occasional families are identified with multiple affected persons (Oliveira 1992). The dearth of such families and the reduced penetrance of MD make classic linkage analysis difficult.
We identified a Chilean family segregating autosomal dominant MD over three generations and completed a genome-wide linkage scan using the Affymetrix GeneChip® Mapping 50K array. Five family members had definite MD, one individual had possible MD, 5 individuals were unaffected, and 4 individuals were too young to classify. Multi-point parametric linkage analysis assuming dominant inheritance and using DNA-Chip Analyzer software (dChip) (www.dchip.org) identified probable linkage to chromosome 1q32.1-q32.3 with a maximum LOD score of 2.36. The candidate gene interval determined by haplotype reconstruction spans 8.3 Mb (201.71- 210.29cM) and includes 79 known genes. No deafness locus maps to this region. The next linkage peak greater than 1 in this family was a LOD score of 1.66 at 17p12. This region spans 382 kb (12.65 – 13.03cM) and includes 6 genes.
Our study is significant because it identifies a locus for MD on 1q32. Since the phenotypes associated with sporadic and familial MD are indistinguishable, the identification of the causative gene in this family may have relevance to the definitive diagnosis of MD in sporadic causes. Furthermore, since little is known about MD and its initiating factors, the identification of a genetic contribution to this disease may help to clarify disease pathogenesis and possibly lead to better therapies.