Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Earlier studies in the tropical Indo‐Pacific have grossly underestimated the richness of macrofauna species at spatial scales relevant to conservation and management as a result of insufficient collecting and sorting effort. A massive collecting effort involving 400 day‐persons at 42 discrete stations on a 295‐km2 site on the west coast of New Caledonia, south‐west Pacific, revealed 2738 species of marine molluscs. This is several times the number of species recorded from any area of comparable extension anywhere in the world. Spatial and habitat heterogeneity is high with 32% of the species collected at a single station. With 20% of the species represented by single specimens (0.4% of all catches), rare species make up a considerable proportion of the fauna. This justifies the parallel drawn between coral reefs and rain forests in terms of species diversity. The real richness of many soft‐bodied marine taxa is probably underestimated, as evidenced by the fact that 28.5% of the mollusc species present at the study site are represented in the samples only by empty shells. © 2002 The Linnean Society of London, Biological Journal of the Linnean Society, 2002, 75, 421–436.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

In this article, we propose a survey of the use of bipolarity in argumentation frameworks. On the one hand, the notion of bipolarity relies on the presence of two kinds of entities that have a diametrically opposed nature and that represent repellent forces (a positive entity and a negative entity). The notion exists in various domains (for example with the representation of preferences in artificial intelligence, or in cognitive psychology). On the other hand, argumentation process is a promising approach for reasoning, based on the construction and the comparison of arguments. It follows five steps: building the arguments, defining the interactions between these arguments, valuating the arguments, selecting the most acceptable arguments and, finally, drawing a conclusion. Using the nomenclature proposed by Dubois and Prade, this article shows on various applications, and with some formal definitions, that bipolarity appears in argumentation (in some cases if not always) and can be used in each step of this process under different forms. C 2008 Wiley Periodicals, Inc.

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.

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Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.