Although it is accepted that idiopathic generalized epilepsy (IGE) is strongly, if not exclusively, influenced by genetic factors, there is little consensus on what those genetic influences may be, except for one point of agreement: epilepsy is a "channelopathy." This point of agreement has continued despite the failure of studies investigating channel genes to demonstrate the primacy of their influence on IGE expression. The belief is sufficiently entrenched that the more important issues involving phenotype definition, data collection, methods of analysis, and the interpretation of results have become subordinate to it. The goal of this article is to spark discussion of where the study of epilepsy genetics has been and where it is going, suggesting we may never get there if we continue on the current road. We use the long history of psychiatric genetic studies as a mirror and starting point to illustrate that only when we expand our outlook on how to study the genetics of the epilepsies, consider other mechanisms that could lead to epilepsy susceptibility, and, especially, focus on the critical problem of phenotype definition, will the major influences on common epilepsy begin to be understood.

BACKGROUND: Familial pulmonary arterial hypertension (FPAH) is a rare, autosomal-dominant, inherited disease with low penetrance. Mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in at least 70% of FPAH patients. However, the lifetime penetrance of these BMPR2 mutations is 10% to 20%, suggesting that genetic and/or environmental modifiers are required for disease expression. Our goal in this study was to identify genetic loci that may influence FPAH expression in BMPR2 mutation carriers.METHODS: We performed a genome-wide linkage scan in 15 FPAH families segregating for BMPR2 mutations. We used a dense single-nucleotide polymorphism (SNP) array and a novel multi-scan linkage procedure that provides increased power and precision for the localization of linked loci.RESULTS: We observed linkage evidence in four regions: 3q22 ([median log of the odds (LOD)= 3.43]), 3p12 (median LOD) = 2.35), 2p22 (median LOD = 2.21), and 13q21 (median LOD = 2.09). When used in conjunction with the non-parametric bootstrap, our approach yields high-resolution to identify candidate gene regions containing putative BMPR2-interacting genes. Imputation of the disease model by LOD-score maximization indicates that the 3q22 locus alone predicts most FPAH cases in BMPR2 mutation carriers, providing strong evidence that BMPR2 and the 3q22 locus interact epistatically.CONCLUSIONS: Our findings suggest that genotypes at loci in the newly identified regions, especially at 3q22, could improve FPAH risk prediction in FPAH families. We also suggest other targets for therapeutic intervention. J Heart Lung Transplant 2010;29:174-80 (C) 2010 International Society for Heart and Lung Transplantation. All fights reserved.

Background: Genetic markers in the serotonin transporter are associated with panic disorder (PD). The associated polymorphisms do not include the serotonin transporter-linked polymorphic region and display no obvious functional attributes. A common polymorphism (rs3813034) occurs in one of the two reported polyadenylation signals for the serotonin transporter and is in linkage disequilibrium with the PD-associated markers. If functional, rs3813034 might be the risk factor that explains the association of the serotonin transporter and PD.Methods: Quantitative polymerase chain reaction on human brain samples (n = 65) and lymphoblast cultures (n = 71) was used to test rs3813034 for effects on expression of the polyadenylation forms of the serotonin transporter. rs3813034 was also tested for association in a sample of PD cases (n = 307) and a control sample (n = 542) that has similar population structure.Results: The balance of the two polyadenylation forms of the serotonin transporter is associated with rs3813034 in brain (P < .001) and lymphoblasts (p < .001). The balance of the polyadenylation forms is also associated with gender in brain only (p < .05). Association testing of rs3813034 in PD identified a significant association (p = .0068) with a relative risk of 1.56 and 1.81 for the heterozygous and homozygous variant genotypes, respectively.Conclusions: rs3813034 is a functional polymorphism in the serotonin transporter that alters the balance of the two polyadenylation forms of the serotonin transporter. rs3813034 is a putative risk factor for PD and other behavioral disorders that involve dysregulation of serotonergic neurotransmission.

The fungal cell wall is vital for growth, development, and interaction of cells with their environment. The response to cell wall damage is well understood from studies in the budding yeast Saccharomyces cerevisiae, where numerous cell wall integrity (CWI) genes are activated by transcription factor ScRlm1. Prior evidence suggests the hypothesis that both response and regulation may be conserved in the major fungal pathogen Candida albicans. We have tested this hypothesis by using a new C. albicans genetic resource: we have screened mutants defective in putative transcription factor genes for sensitivity to the cell wall biosynthesis inhibitor caspofungin. We find that the zinc finger protein CaCas5, which lacks a unique ortholog in S. cerevisiae, governs expression of many CWI genes. CaRlm1 has a modest role in this response. The transcriptional coactivator CaAda2 is also required for expression of many CaCas5-dependent genes, as expected if CaCas5 recruits CaAda2 to activate target gene transcription. Many caspofungin-induced C. albicans genes specify endoplasmic reticulum and secretion functions. Such genes are not induced in S. cerevisiae, but promote its growth in caspofungin. We have used a new resource to identify a key C. albicans transcriptional regulator of CWI genes and antifungal sensitivity. Our gene expression findings indicate that both divergent and conserved response genes may have significant functional roles. Our strategy may be broadly useful for identification of pathogen-specific regulatory pathways and critical response genes.

The ESCRT-I, -II, and -III protein complexes function to create multivesicular bodies (MVBs) for sorting of proteins destined for the lysosome or vacuole. Prior studies with Saccharomyces cerevisiae have shown that the ESCRT-III protein Snf7p interacts with the MVB pathway protein Bro1p as well as its homolog Rim20p. Rim20p has no role in MVB formation, but functions in the Rim101p pH-response pathway; Rim20p interacts with transcription factor Rim101p and is required for the activation of Rim101p by C-terminal proteolytic cleavage. We report here that ESCRT-III proteins Snf7p and Vps20p as well as all ESCRT-I and -II proteins are required for Rim101p proteolytic activation in S. cerevisiae. Mutational analysis indicates that the Rim20p N-terminal region interacts with Snf7p, and an insertion in the Rim20p "Bro1 domain" abolishes this interaction, as determined with two-hybrid assays. Disruption of the MVB pathway through mutations affecting non-ESCRT proteins does not impair Rim101p processing. The relationship between the MVB pathway and Rim101p pathway is conserved in Candida albicans, because mutations in four ESCRT subunit genes abolish alkaline pH-induced filamentation, a phenotype previously seen for rim101 and rim20 mutants. The defect is suppressed by expression of C-terminally truncated Rim101-405p, as expected for mutations that block Rim101p proteolytic activation. These results indicate that the ESCRT complexes govern a specific signal transduction pathway and suggest that the MVB pathway may provide a signal that regulates pH-responsive transcription.

ABSTRACT The Candida albicans cell wall participates in both growth and morphological transitions between yeast and hyphae. Our studies here focus on Dfg5p and Dcw1p, two similar proteins with features of glycosylphosphatidylinositol-linked cell surface proteins. Mutants lacking Dfg5p are defective in alkaline pH-induced hypha formation; mutants lacking Dcw1p have no detected hypha formation defect. Both homozygote-triplication tests and conditional expression strategies indicate that dfg5 and dcw1 mutations are synthetically lethal. Therefore, Dfg5p and Dcw1p share a function required for growth. Epitope-tagged Dfg5p, created through an insertional mutagenesis strategy, is found in cell membrane and cell wall extract fractions, and endoglycosidase H digestion shows that Dfg5p undergoes N-linked mannosylation. Surprisingly, Dfg5p is required for expression of the hypha-specific gene HWP1 in alkaline media. Because Dfg5p is a cell surface protein, it is poised to generate or transmit an external signal required for the program of hypha-specific gene expression.