GN Shubha

Bio: GN Shubha is an academic researcher from National Institute of Mental Health and Neurosciences. The author has contributed to research in topics: Serotonin transporter & Duchenne muscular dystrophy. The author has an hindex of 4, co-authored 4 publications receiving 60 citations.

Duchenne muscular dystrophy: A clinical, histopathological and genetic study at a neurology tertiary care center in southern India

Abstract: Background : Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy that affects young boys and the dystrophin gene on the X chromosome has been found to be associated with the disorder. Materials and Methods : In this prospective study, 112 clinically diagnosed DMD patients had muscle biopsy and were tested for exon deletions. Genotyping was also carried out at STR44, STR45, STR49 and STR 50 markers in 15 families. Results : Of the 112 clinically suspected DMD patients, the diagnosis of DMD was confirmed by histopathology and/or genetics in 101 patients. The mean age of onset was 3.1±1.44 years (1-6 years) and the mean age at presentation was 8.0±3.1 years (1.1-18.0 years). Delayed motor milestones were present in 63 (62.3%) patients. The mean creatine kinase value was 11822.64±8206.90 U/L (1240-57,700). Eighty-four patients had muscle biopsy and immunohistochemistry was done in 60 muscle samples, all of which demonstrated absence of dystrophin staining. Of the 60 dystrophin-negative cases, 73% showed deletion of at least one exon. Single exon deletion was found in 20.4%. Distal hotspot Exons 45, 47, 49 and 50 were the commonly deleted xenons and the deletion rates were 36%, 35%, 33.7% and 38.5% respectively. Conclusions : In this study population in south India the deletion rate was 73% and were more frequent in the distal end exon. With the availability of genetic analysis, the first investigation of choice in DMD should be genetic studies and muscle biopsy should be considered only if the genetic tests are negative or not available.

Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a South Indian population

Abstract: Background and Objectives : Serotonin transporter polymorphisms, 5-HTTVNTR and 5-HTTLPR, have been found to be associated with obsessive-compulsive disorder (OCD) and particularly with neurotic characteristics. In the present study we looked for an association between OCD and these polymorphisms in OCD patients and controls of south Indian origin. Methods: 5-HTTVNTR and 5-HTTLPR/rs25531 were genotyped in 93 OCD patients and 92 healthy controls. The allelic distribution and genotype frequency in cases and controls were compared using chi square test. In order to test for the effects of genotype on heterogeneity of the illness, linear regression analysis was undertaken for co-morbid depression status and YBOCS score (severity index). Results: There was no significant association with the 5-HTTVNTR or the 5-HTTLPR polymorphism. No significant association of OCD with the 5-HTTLPR genotype was found even on inclusion of the rs25531 locus, which is part of the transcription factor binding site as reported in earlier studies. However, severity of the illness showed a modest association with the dominant model. Interpretation and Conclusions : Our data show that genetic variation in the SLC6A4 gene regulatory region may not have a significant effect on OCD in the present population. Further replication in a large and independent cohort with an equal number of female subjects would help to ascertain if the absence of association in this cohort is due to the nullifying effect of the larger proportion of male subjects in our sample population. The marginal effect of the 5-HTTLPR (A/G) genotype obtained on linear regression with disease severity is suggestive of a potential role for this locus in the disease process.

Identification of interaction between serotonin transporter and glycogen synthase kinase-3β gene polymorphisms: role in susceptibility to bipolar disorder

Abstract: Background: Genetic correlates of diseases of complex inheritance may include variations in several genes lying within a network of linked biological processes. Synaptic mechanisms, such as serotonin neurotransmission and second (third) messengers (e.g., glycogen synthase kinase [GSK]), have been implicated in susceptibility to mood disorders, the actions of therapeutic drugs and manipulation of circadian rhythms. A better understanding of such gene networks may be useful to understand the biology and treatment of mood disorders. Methods: We studied the association between serotonergic and GSK-mediated signaling networks with bipolar affective disorder (BPAD). We analyzed two single nucleotide polymorphisms (SNPs) in the HTR2A gene, a promoter SNP in SLC6A4 and a promoter SNP in the GSK3B gene in BPAD individuals and matched controls. A multifactor dimensionality reduction tool was employed to study gene–gene interactions and analyze multilocus genotype combination associations with high- or low-risk of B...

Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies.

Abstract: Molecular genetics of obsessive–compulsive disorder: a comprehensive meta-analysis of genetic association studies

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

Abstract: Background and purpose Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. Methods A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. Results The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. Conclusions The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

Behavioural Genetics of the Serotonin Transporter

Abstract: The serotonin transporter is a key regulator of the bioavailability of serotonin and therefore any modulation in the expression or action of the transporter would be expected to have consequences on behaviour. The transporter has therefore become a target for pharmaceutical intervention in behavioural and mood disorders. The search for polymorphic variants in the transporter that would associate with neurological disorders has been extensive but has become focused on two domains which are both termed variable number tandem repeat (VNTR) polymorphisms. Both of these VNTRs are in non-coding DNA and therefore proposed to be mechanistically involved in a disorder through their ability to modulate transcriptional or post-transcriptional regulation of the transporter. The most extensively studied is in the promoter and is a bi-allelic insertion/deletion found in the 5′ promoter region of the gene 1.2 kb upstream of the transcriptional start site. This VNTR, termed, 5-HTTLPR was initially identified as two variants containing either, 14 (short/deletion) or 16 (long/insertion) copies of a 22 bp repeat. A second widely studied VNTR found in the non-coding region of the transporter is located within intron 2 and comprises 9, 10 or 12 copies of a 16–17 bp repeat termed, STin2.9, STin2.10 and STin2.12, respectively. These VNTR polymorphisms have been associated with a range of behavioural and psychiatric disorders including depression, OCD, anxiety and schizophrenia, however often the lack of reproducibility in different cohorts has led to debate on the actual association of the polymorphisms with this extensive range of neurological conditions. Here we review these two polymorphic VNTRs in depth and relate that to pharmaceutical response, their ability to regulate differential transporter expression, their core involvement in gene-environment interaction and their genetic association with specific disorders.