Sexual orientation and courtship behavior in Drosophila are regulated by fruitless (fru), the first gene in a branch of the sex-determination hierarchy functioning specifically in the central nervous system (CNS). The phenotypes of new fru mutants encompass nearly all aspects of male sexual behavior. Alternative splicing of fru transcripts produces sex-specific proteins belonging to the BTB-ZF family of transcriptional regulators. The sex-specific fru products are produced in only about 500 of the 10(5) neurons that comprise the CNS. The properties of neurons expressing these fru products suggest that fru specifies the fates or activities of neurons that carry out higher order control functions to elicit and coordinate the activities comprising male courtship behavior.

In a study of 530 individuals with non-syndromic, sensorineural hearing loss, we identified 18 mutations at connexin 26 (Cx26), four of which are novel (À23G4T, I33T, 377_383dupTCCGCAT, W172R) and the remaining 14 (ivs1 þ 1G4A, M1V, 35delG, W24X, I35S, V37I, R75W, W77X, 312del14, E120del, Q124X, Y136X, R143W, R184P) being mutations previously described. To gain insight into functional consequences of these mutations, cellular localization of the mutant proteins and their ability to permit lucifer yellow transfer between cells was studied in seven of them (W24X, I33T, I35S, R75W, E120del, W172R and R184P). I35S and R184P showed impaired trafficking of the protein to the plasma membrane. I33T, R75W, E120del and W172R showed predominantly membrane localization but did not form functional gap junction channels. Surprisingly, W24X, a protein-truncating mutation, apparently permits formation of a full-length protein, perhaps due to a stop codon read-through mechanism. These results provide further evidence that Cx26 mutations affect gap junction activity by mis-regulation at multiple levels.

A novel idiopathic epilepsy locus has been mapped on chromosome 3q13.3-q21, as evident by presence of significant genetic linkage. Identification of novel, rare missense CASR variants at evolutionary-conserved residues in epilepsy patients and CASR expression in various subregions of human brain raises an interesting possibility of involvement of CASR in pathophysiology of epileptic disorders.

Summary:Purpose: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls.Methods: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. Results:We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region.Conclusions: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

Despite the distinctive clinical and electroencephalographic features known for five decades, even today, juvenile myoclonic epilepsy (JME) is frequently unrecognised and misdiagnosed in both developed and developing countries. Utilising 183 JME probands belonging to the South Indian state of Kerala, assembled through a tertiary referral centre for molecular genetic studies, we explored the phenotypic peculiarities, clinical genetics, and problems and pitfalls in the diagnosis of JME. At referral, only six (3.3%) patients carried the diagnostic label of JME, default in diagnosis resulted from failure to elicit the history of myoclonic jerks by the referring physicians. During the mean delay of 8.6 +/- 7.0 years in diagnosing JME, seizure control in the majority was poor due to inappropriate antiepileptic drug (AED) therapy. A history of epileptic seizures was obtained in 6.2% of the first-degree and 2.2% of the second-degree relatives of the probands; 37.7 and 11.1% of them, respectively, were diagnosed as JME. Although most of the clinical features of our cohort were in accordance with the literature, two notable differences we observed were the relatively increased occurrence of absence seizures and low frequency of photoparoxysmal responses. Although the variability in the clinical characteristics of JME may be apparent due to differences in the ascertainment of the data, they may well be an expression of a true clinical heterogeneity, and are in accordance with the complex and variable mode of inheritance and conflicting linkage studies reported for this syndrome from different ethnic groups.