An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to Ϸ2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism͞20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family-and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes.

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurinrelated genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin ␥ catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis. S chizophrenia is a severe psychiatric condition that affects Ϸ1% of the population worldwide (1). Studies of the inheritance of schizophrenia have revealed that it is a multifactorial disease characterized by multiple genetic susceptibility elements, each contributing a modest increase in risk (2). Family linkage studies and studies of chromosomal abnormalities associated with schizophrenia have identified a number of schizophrenia susceptibility loci (2, 3). Such loci provide a basis for higher resolution genetic studies and a criterion for assessment of potential candidate genes. In addition to direct genetic analysis, a longstanding body of pharmacological studies has led to the prevailing hypotheses that dysfunction of dopaminergic or Nmethyl-D-aspartate (NMDA) receptor-mediated signaling are major contributing factors in schizophrenia pathogenesis (4-6).Calcineurin is a calcium-dependent serine͞threonine protein phosphatase that is highly expressed in the CNS (7,8). Calcineurin consists of a heterodimer composed of a regulatory subunit, CNB, and a catalytic subunit, CNA (7, 8). There are three different CNA isoforms encoded by distinct genes. Calcineurin activity plays a key role in the downstream regulation of dopaminergic signal transduction (9) and in the induction of certain forms of N-methyl-D-aspartate receptor-dependent synaptic plasticity (10, 11). Thus, calcineurin function could comprise a critical link between dopaminergic and glutamatergic signaling.In an accompanying study, we report that forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities that is strikingly reminiscent of altered behaviors observed in schizophrenia patients (12). Based on these findings, we decided to further investigate the potential involvement of calcineurin dysfunction in schizophrenia etiology by directly testing for genetic association of calcineurin-related candidate genes with schizophrenia. We prioritized examination of genes encoding calcineurin subunits or calcineurin-related molecules that map to schizophrenia susceptibility loci. We present direct genetic evidence for association of the PPP3CC gene with schizophrenia. PP...

The recessive gene rhm confers chlorotic-lesion resistance to Bipolaris maydis race O, the southern corn leaf blight pathogen, in otherwise susceptible maize plants. Because of inconsistencies encountered in scoring the disease on mature plants in the field, an assay was developed to monitor the expression of this gene in maize seedlings under controlled conditions. One hundred and two related F3 families from the cross RH95rhm x B73 were inoculated with conidia of B. maydis race O, and the genotype at the rhm locus of each F2 parent was deduced from the reactions observed in the progeny seedlings. The F2 genomes were reconstituted by extracting DNA from leaf tissue pooled from 30-36 F3 progeny plants per family. The seedling disease ratings were analyzed together with the segregation scores for 14 single-copy DNA probes. Our results indicate that rhm is tightly linked to two restriction fragment length polymorphism (RFLP) marker loci (UMC85 and p144) that map to the short arm of chromosome 6. In addition, a rapid assay based on the polymerase chain reaction was used to confirm the linkage between rhm and the p144 RFLP marker locus in a second unrelated F2 population.

No abstract

No abstract

No abstract