Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.

A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

Hemorrhage is uncommon in new Alzheimer family with Flemish amyloid precursor protein mutation.

BACKGROUND: Most mutations in the amyloid precursor protein (APP) gene have been associated with familial Alzheimer disease (AD); however, some mutations within the Abeta-coding sequence have been described in families with recurrent cerebral hemorrhage. The APPAla692Gly (Flemish) mutation was reported in a family in which affected members developed hemorrhagic stroke, progressive dementia, or both. OBJECTIVE: To describe clinical, neuropathologic, and genetic features of a family of British origin with the Flemish APP mutation. METHODS: Clinical features of the proband and two affected relatives were obtained by history, examination, and medical record review. Some information on deceased affected relatives was obtained by informant interview. Neuropathologic examination was carried out on one case. DNA studies were carried out on three affected and three unaffected individuals. RESULTS: Presenile dementia was present in a pattern consistent with dominant inheritance, with the APP692 mutation being found in all affecteds and no unaffecteds. The proband also had a cerebral hemorrhage, but was the only one of five affecteds to have this complication. Neuropathologic examination confirmed AD, congophilic angiopathy, and hemorrhagic infarction. CONCLUSIONS: This expands the number of families reported with mutations in the coding region of the amyloid precursor protein gene. Cerebral hemorrhage appears to be less frequent in this family than in the previously reported Flemish pedigree with the same mutation.

Similar early clinical presentations in familial and non-familial frontotemporal dementia.

BACKGROUND: It is unclear whether there are early clinical features that can distinguish between patients with familial and non-familial frontotemporal dementia (FTD). OBJECTIVE: To compare the clinical features of FTD cases who have tau gene mutations with those of cases with a family history of FTD but no tau gene mutation, and with sporadic cases with neither feature. METHODS AND RESULTS: Comparisons of the behavioural, cognitive, and motor features in 32 FTD patients (five positive for tau gene mutations, nine familial but tau negative, and 18 tau negative sporadic) showed that age of onset and duration to diagnosis did not differ between the groups. Apathy was not observed in tau mutation positive cases, and dysexecutive signs were more frequent in familial tau mutation negative cases. Memory deficits and behavioural changes were common in all groups. CONCLUSIONS: In comparison with other neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neither tau gene mutations nor strong familial associations confer earlier disease susceptibility.

Baculoviruses expressing the human familial Alzheimer's disease presenilin 1 mutation lacking exon 9 increase levels of an amyloid beta-like protein in Sf9 cells.

Presenilin 1 (PS1) plays a pivotal role in the production of the amyloid-beta protein (Abeta) that is central to the pathogenesis of Alzheimer's disease. PS1 regulates the intramembranous proteolysis of a 99-amino-acid C-terminal fragment of the amyloid precursor protein (APP-C99), a cleavage event that releases Abeta following a reaction catalyzed by an enzyme termed 'gamma-secretase'. The molecular mechanism of PS1-mediated, gamma-secretase cleavage remains largely unresolved. In particular, controversy surrounds whether PS1 includes the catalytic site of the gamma-secretase protease or whether instead PS1 mediates gamma-secretase activity indirectly, perhaps by regulating the trafficking or presentation of substrates to the 'authentic' protease, which may be a molecule distinct from PS1. To address this issue, the baculovirus expression system was used to co-express: (i) APP-C99; (ii) a pathogenic, constitutively active mutant form of PS1 lacking exon 9 (PS1DeltaE9); (iii) nicastrin and (iv) tropomyosin in Spodoptera frugiperda (Sf9) cells. Cells infected with APP-C99 alone produced an Abeta-like species, and levels of this species were enhanced by the addition of baculoviruses bearing the PS1DeltaE9 mutation. The addition to APP-C99-infected cells of baculoviruses bearing nicastrin, also a transmembrane protein, had a neutral or inhibitory effect on the reaction; tropomyosin viruses had the same effect as nicastrin viruses. These results suggest that PS1DeltaE9 molecules expressed in Sf9 cells retain the ability to modulate Abeta levels. Baculoviral-expressed PS1DeltaE9 provides a source of microgram quantities of bioactive molecules for use as starting material for purifying and reconstituting gamma-secretase activity from its individual purified component parts.