"Cri-du-chat" syndrome in a patient born to a mother with a paracentric inversion of chromosome 5q.

We report the case of a female child presented at birth with hypotonia, growth retardation and respiratory distress. Chromosome study from peripheral blood showed a 46,XX,del(5)(p14pter) karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced paracentric inversion of long arms of one chromosome 5, giving the karyotype 46,XX,inv(5)(q12q32), whereas paternal karyotype was normal. The maternal abnormality was confirmed by fluorescence in situ hybridization (FISH) and was not present in the daughter's metaphases. Microsatellite analysis in the proposita and her parents permitted us to conclude that the deleted chromosome 5 was paternal in origin, as usually described. Therefore, as might have been expected, maternal paracentric inversion of chromosome 5q and "cri-du-chat syndrome" presented by the daughter were not related.

Neurons overexpressing mutant presenilin-1 are more sensitive to apoptosis induced by endoplasmic reticulum-Golgi stress.

Most early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, ps1 and ps2. FAD-linked mutant PS1 alters proteolytic processing of the amyloid precursor protein and increases vulnerability to apoptosis induced by various cell stresses. In transfected cell lines, mutations in ps1 decrease the unfolded-protein response (UPR), which is the response to the increased amounts of unfolded proteins that accumulate in the endoplamic reticulum (ER), indicating that these mutations may increase vulnerability to ER stress by altering the UPR signalling pathway. Here we report that, in primary cultured neurons from cortices of transgenic mice, overexpression of mutated PS1 (M146L mutation) but not PS1 wild-type (wt) enhanced spontaneous neuronal apoptosis that involved oxidative stress and caspase activation. In PS1M146L cultures, neurons displaying immunoreactivity for human PS1 were threefold more vulnerable to spontaneous apoptosis than the overall neuronal population. In addition, PS1M146L transgenic neurons were more sensitive to apoptosis induced by various stresses, including two ER-Golgi toxins, nordihydroguaiatric acid and brefeldin A (also known to induce UPR), as well as staurosporine. In contrast, PS1 wt transgenic neurons were resistant to apoptosis induced by Golgi-ER toxins but displayed a comparable vulnerability to staurosporine. Our study demonstrates that, as previously reported, overexpression of FAD-linked mutant PS1 enhances neuronal vulnerability to spontaneous and induced apoptosis. In addition, we show that this vulnerability was correlated with mutant PS1 protein expression and that PS1 wt overexpression selectively prevented ER-Golgi stress-induced apoptosis. These data indicate that PS1 interferes with a specific apoptotic pathway that results from a dysfunction of the ER-Golgi compartment.