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According to the prevailing 'amyloid cascade hypothesis,' genetic dementias such as Alzheimer's disease and familial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD ([FDD.sub.KI/+]) genetically congruous with human cases. [FDD.sub.KI/+] mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. [Bri2.sup.+/-] mice exhibit synaptic and memory deficits similar to [FDD.sub.KI/+] mice, and memory loss of [FDD.sub.KI/+] mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy. amyloid-[beta] precursor protein | ITM2b doi/ 10.1073/pnas.1011689107

Heritable mutations, known as inborn errors of metabolism, cause numerous devastating human diseases, typically as a result of a deficiency in essential metabolic products or the accumulation of toxic intermediates. We have isolated a missense mutation in the Drosophila sugarkill (sgk) gene that causes phenotypes analogous to symptoms of triosephosphate isomerase (TPI) deficiency, a human familial disease, characterized by anaerobic metabolic dysfunction resulting from pathological missense mutations affecting the encoded TPI protein. In Drosophila, the sgk gene encodes the glycolytic enzyme TPI. Our analysis of sgk mutants revealed TPI impairment associated with reduced longevity, progressive locomotor deficiency, and neural degeneration. Biochemical studies demonstrate that mutation of this glycolytic enzyme gene does not result in a bioenergetic deficit, suggesting an alternate cause of enzymopathy associated with TPI impairment.

In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA 1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.

Fatal familial insomnia, a genetic disease with neurological symptoms, is caused by an abnormal form of a protein called prion protein. Analysis of brain tissue from two related patients who died from fatal familial insomnia found prion protein. This protein was different from that found in brain tissue of three people who died from Creutzfeldt-Jakob disease, another prion-associated neurological disease. DNA analysis of the gene for prion protein in both patients found that the gene had a mutation at position 178 that resulted in a substitution of the amino acid asparagine for aspartic acid in the protein. A living family member who had the disease had the same mutation. Eleven of 29 relatives who were not affected by the disease also had the mutation.

There has been a change in the epidemiology of tinea capitis over the past 40 years. Today, the major organism responsible is Trichophyton tonsurans, a dermatophyte that accounts for more than 90% of all ringworm infections of the scalp in the US It replaces Microsporum audouinii and M canis, which were associated with ringworm epidemics in the 1940s. Tinea capitis manifests itself in forms ranging from a mild flaking of the scalp to an intense inflammatory reaction. A study is reported that investigated the prevalence of undiagnosed tinea capitis in other members of households where there were children with documented tinea capitis. The high incidence of infection of other household members underscores the need for consistent follow-up of those with persistent infection who can reinfect others. Large-scale studies are needed to confirm these findings and to develop screening and management techniques for tinea capitis.