Partial loss of desmin expression due to a leaky splice site variant in the human DES gene is associated with neuromuscular transmission defects.

Recessive desminopathies are rare and often present as severe early-onset myopathy. Here we report a milder phenotype in three unrelated patients from southern India (2 M, 1F) aged 16, 21, and 22 years, who presented with childhood-onset, gradually progressive, fatigable limb-girdle weakness, ptosis, speech and swallowing difficulties, without cardiac involvement. Serum creatine kinase was elevated, and repetitive nerve stimulation showed decrement in all. Clinical improvement was noted with pyridostigmine and salbutamol in two patients. All three patients had a homozygous substitution in intron 5: DES(NM_001927.4):c.1023+5G>A, predicted to cause a donor splice site defect. Muscle biopsy with ultrastructural analysis suggested myopathy with myofibrillar disarray, and immunohistochemistry showed partial loss of desmin with some residual staining, while western blot analysis showed reduced desmin. RT-PCR of patient muscle RNA revealed two transcripts: a reduced normal desmin transcript and a larger abnormal transcript suggesting leaky splicing at the intron 5 donor site. Sequencing of the PCR products confirmed the inclusion of intron 5 in the longer transcript, predicted to cause a premature stop codon. Thus, we provide evidence for a leaky splice site causing partial loss of desmin associated with a unique phenotypic presentation of a milder form of desmin-related recessive myopathy overlapping with congenital myasthenic syndrome.

Clustering of Juvenile Canavan disease in an Indian community due to population bottleneck and isolation: genomic signatures of a founder event.

Mild/juvenile Canavan disease (M/JCD) is less frequently reported in the literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel NM_000049.4(ASPA):c.526G>A variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile-onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, led us to speculate the possibility of a founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event in TDC, such as a high fixation index, increased runs of homozygosity and identity-by-descent in the absence of consanguinity; a large haplotype with high linkage disequilibrium among markers comprising the pathogenic variant; a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.

Evidence for genetic linkage between a polymorphism in the GNAS gene and malaria in South Indian population.

The complex imprinted GNAS locus which encodes G-alpha subunit (Gαs) is involved in a number of G-protein coupled signaling pathways in eukaryotic cells. Erythrocyte invasion by Plasmodium falciparum parasites is significantly regulated by protein of GNAS gene. This study was designed to evaluate the association between single nucleotide polymorphisms (SNPs) present in GNAS locus and susceptibility to malaria. In this case control study, individuals affected by P. falciparum malaria (n=230), Plasmodium vivax malaria (n=230) and normal controls (n=230) were tested for the association of eighteen (18) known SNPs to evaluate their role in the onset of the disease. There was no significant difference in genotype frequencies of all the SNPs tested between P. falciparum and P. vivax affected individuals. However, when Bonferroni correction for multiple comparisons were performed as a control, our results demonstrated alleles and genotypes of rs7121: C>T (NC_000020.10:g.57478807C>T), a silent polymorphism situated in the exon 5, were significantly (p<0.05) associated with susceptibility to malaria in the South Indians participants. Our results demonstrate that population specific polymorphisms that exist in GNAS gene may alter the risk of occurrence of malaria.

Study of the association of serotonin transporter triallelic 5-HTTLPR and STin2 VNTR polymorphisms with lithium prophylaxis response in bipolar disorder.

The 5-hydroxy tryptamine transporter (5-HTT) gene has been previously implicated in lithium response, but the roles of the triallelic 5-HTT linked promoter region (5-HTTLPR) and variable number tandem repeats in the second intron [serotonin transporter intron 2 (STin2)] have not been reported. We examined these polymorphisms in 122 patients with bipolar I disorder, among which 49 patients were classified as good responders, 49 as nonresponders, and 24 as partial responders to lithium prophylaxis. We observed significant variation in the genotype frequencies of STin2 polymorphism among the response groups (P=0.02). There was also a significant association of haplotype consisting of the S allele of 5-HTTLPR and 10 repeat allele of STin2 with lithium response (P=0.01) and no such relationship was found with 5-HTTLPR variants. Our data support preliminary information of a possible association of STin2 and its combined effect with 5-HTTLPR variants with lithium response and also suggest that lithium is likely to be more effective for patients carrying 5-HTT polymorphisms associated with reduced transcriptional activity.