Anuranjan Anand

Control of Male Sexual Behavior and Sexual Orientation in Drosophila by the fruitless Gene

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.

Contribution of connexin26 ( GJB2 ) mutations and founder effect to non-syndromic hearing loss in India

Congenital hearing loss has been documented to occur in 1 of 1000 live births, with over half of these cases predicted to be hereditary in nature.1,2 Most hereditary hearing loss is inherited in a recessive manner, accounting for approximately 85% of non-syndromic hearing loss (NSHL). Deafness is an extremely genetically heterogeneous disorder, shown by the fact that 33 loci for recessive NSHL and 39 loci for dominant NSHL have been mapped to date (updated regularly on the Hereditary Hearing Loss Homepage: http://dnalab-www.uia.ac.be/dnalab/hhh/index.html). In populations with increased levels of consanguinity, such as India,3 congenital hearing loss is even higher. According to the 47th Round of the National Sample Survey Organisation (NSSO) taken in 1991 (http://www.healthlibrary.com/), 3 242 000 subjects over the age of 5 have a hearing disability, which is defined as a hearing impairment of 60 decibels and above in the better ear to total loss of hearing in both ears. Prelingual recessively inherited deafness has long been recognised in India. A significant number of the deafness loci have been discovered or found in the Indian population, facilitated by the large extended families and high rates of consanguinity. Seven deafness loci are currently known to be associated with deafness in India. These include DFNB3,4 DFNB5,5 DFNB6,6 DFNB7/B11,7 DFNB15,8 DFNB17,9 and DFNB18.10 In four of these seven cases, the associated gene has been cloned: transmembrane cochlear expressed gene 1 ( TMC1 ) for DFNB7/B11,11 myosin XVA ( MYO15A ) for DFNB3,4,12 transmembrane inner ear expressed gene ( TMIE ) for DFNB6,13 and harmonin for DFNB18.14 In many parts of the world, deafness associated with the DFNB1 locus on chromosome 13q11 is the most prevalent. Two genes localised to this chromosomal region have been implicated in deafness, including connexin26 (Cx26, gene symbol GJB2 …

A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy.

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.

An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene

To identify the disease locus in a three‐generation south Indian family having several of its members affected with idiopathic epilepsy.

Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss.

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 (−23G>T, I33T, 377_383dupTCCGCAT, W172R) and the remaining 14 (ivs1+1G>A, 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.

The polyglutamine motif is highly conserved at the Clock locus in various organisms and is not polymorphic in humans

Abstract. Circadian rhythms play a central role in diverse physiological phenomena and the recent years have witnessed the identification of a number of genes responsible for the maintenance of these rhythms. One of these is the Clock gene, which was first identified in mouse and subsequently in a large number of organisms, including humans. The human Clock gene has been proposed as a possible candidate for disorders affected by alterations of circadian rhythm, including bipolar disorder and schizophrenia. This gene contains a highly conserved polyglutamine motif, that in humans is coded for by CAG repeats. In view of the involvement of CAG repeat expansion in a number of neuro-psychiatric disorders, we have sought to determine the polymorphism status of CAG repeats at the Clock locus in humans. Our analysis of 190 unrelated individuals, who included patients suffering from bipolar disorder and schizophrenia, indicated that the repeat, which consisted of 6 CAG triplets, was not polymorphic in humans. An analysis of the repeat in non-human primates and other organisms revealed that the glutamine stretch is shortest in humans and baboons, and longest in Drosophila and zebrafish. A study of various Drosophila species revealed that the repeat number is highly polymorphic, ranging from 25 to 33 pure glutamine repeats. Unlike most other microsatellites, the CAG repeat stretch at the Clock locus in humans is smaller than its homologues in non-human primates. We propose that glutamine repeat size is functionally important in this gene and thus tightly regulated. The variation in repeat number is probably deleterious to the individual, resulting in the maintenance of a short and invariable repeat structure in the human population.

Clinical characteristics of a South Indian cohort of juvenile myoclonic epilepsy probands

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.

Association analysis of CAG repeats at the KCNN3 locus in Indian patients with bipolar disorder and schizophrenia.

Bipolar affective disorder and schizophrenia are severe behavioral disorders with a lifetime risk of approximately 1% in the population worldwide. There is evidence that these diseases may manifest the phenomenon of anticipation similar to that seen in diseases caused by trinucleotide repeat expansions. A recent report has implicated a potassium channel-coding gene, KCNN3, which contains a polymorphic CAG repeat in its coding region, in schizophrenia and bipolar disorder. We have tried to confirm these findings in Indian patients suffering from bipolar disorder and schizophrenia. No statistically significant evidence for the presence of an excess of longer alleles in the patient population, as compared to ethnically matched controls, was found. However, an analysis of the difference of allele sizes revealed a significantly greater number of patients with schizophrenia having differences of allele sizes > or = 5 when compared to normal controls. This finding may be of functional significance as the KCNN3 protein is thought to act as a tetramer, and a large difference in allele sizes would result in an asymmetric molecule with a different number of glutamine residues in each monomer. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:744-748, 2000.

A clinical study of patients with genetically confirmed Huntington's disease from India

BACKGROUND Clinical data across the globe especially in genetic diseases like Huntingtons disease (HD) is most helpful when collected using standardized formats. This helps in proper comparison of clinical and genetic data. METHODS Herein, we report clinical data on 26 genetically confirmed HD patients from 19 Indian families predominantly from South India. Clinical data and evaluation was performed using standardized formats used by the Huntington Disease Study Group. RESULTS Adult onset HD was commonest while Juvenile HD (onset <20 years) was observed in approximately 15% of patients. Chorea was the commonest presenting symptom (n=23, 88.5%) while remaining presented with psychiatric symptoms (n=3, 11.5%). Impairment of saccades was observed in approximately 75% of patients. Mean (SD) CAG repeats in the abnormal allele was 48.4 (8.7). Total motor score but not the total behavioral score worsens with duration of symptoms. The functional checklist score correlates with total motor score rather than with duration of symptoms. CONCLUSIONS We detail clinical characteristics in genetically confirmed HD patients from a predominantly South Indian cohort. We observed a slightly higher occurrence of Juvenile HD. Functional disabilities in our patients correlate with worsening of motor rather than behavioral symptoms.

Polymorphisms at the DRD2 locus in early-onset alcohol dependence in the Indian population

The susceptibility to alcohol dependence is probably of polygenic origin. Association studies have attempted to identify possible candidate genes that may contribute to the risk to developing dependence. Severe forms of the alcoholism phenotype have been associated with an increased frequency of the Taq A1 allele at the DRD2 locus. Ethnic stratification and non‐comparable phenotype may have contributed to the contradictory results in previous studies. We identified probands, using the Schedules of Assessment of Neuropsychiatry (SCAN) schedule, who had onset of alcohol dependence (ICD‐10) before 25 years of age. Family members were interviewed using the Family Interview for Genetic Studies (FIGS) schedule to identify patients who had two first‐degree relatives with alcohol dependence. Fifty subjects who fulfilled the criteria were selected for the study. These were compared to a normal population from a similar background. The allele frequencies did not differ between the two groups. The Taq1a polymorphism does not seem to be associated with alcoholism in this group of severely affected, young age of onset probands in the southern Indian population.