Studies on Diversed Hetrocyclic Chemical Entitites and Their Application

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A case of Raine syndrome presenting with facial dysmorphy and review of literature

Abstract Background Raine syndrome (RS) – an extremely rare autosomal recessive genetic disorder, is caused by a biallelic mutation in the FAM20C gene. Some of the most common clinical features include generalized osteosclerosis with a periosteal bone formation, dysmorphic face, and thoracic hypoplasia. Many cases have also been reported with oro-dental abnormalities, and developmental delay. Most of the cases result in neonatal death. However, a few non-lethal RS cases have been reported where patients survive till adulthood and exhibits a heterogeneous clinical phenotype. Clinical diagnosis of RS has been done through facial appearance and radiological findings, while confirmatory diagnosis has been conducted through a molecular study of the FAM20C gene. Case presentation A 6-year-old girl was born to healthy third degree consanguineous parents. She presented with facial dysmorphy, delayed speech, and delayed cognition. Radiography showed small sclerotic areas in the lower part of the right femur, and an abnormally-shaped skull with minimal sclerosis in the lower occipital region. Computer tomography scan of the brain revealed mild cortical atrophy, and MRI scan of the brain showed corpus callosal dysgenesis with the absence of the rostral area. Chromosome banding at 500 band resolution showed a normal female karyotype. No quantitative genomic imbalance was detected by aCGH. Further study conducted using Clinical Exome Sequencing identified a homozygous missense variation c.1228 T > A (p.Ser410Thr) in the exon 6 of FAM20C gene – a likely pathogenic variant that confirmed the clinical diagnosis of RS. The variant was confirmed in the proband and her parents using Sanger sequencing. Prenatal diagnosis during subsequent pregnancy revealed heterozygous status of the fetus, and a normal carrier child was delivered at term. Conclusions The syndrome revealed markedly variable presentations such as facial dysmorphy and developmental delay, and was localized to diffuse bone osteosclerosis. Clinical indications, striking radiological findings and molecular testing of FAM20C gene confirmed the diagnosis of RS. A rarity of the disorder and inconsistent phenotype hindered the establishment of genotype-phenotype correlations in RS. Therefore, reporting more cases and conducting further research would be crucial in defining the variable radiologic and molecular defects of the lethal and non-lethal forms of this syndrome

Additional file 1: of A case of Raine syndrome presenting with facial dysmorphy and review of literature

Molecular investigations. The file describes the method used in isolation of genomic DNA, NGS and bioinformatics tools used during analysis. (DOCX 16 kb

Additional file 5: of A case of Raine syndrome presenting with facial dysmorphy and review of literature

Population screening for c.1228T>A (p.Ser410Thr) variant by ARMS-PCR. The file provides details of normal healthy individuals studied for variant (c.1228T>A (p.Ser410Thr)) by ARMS-PCR. (DOCX 15 kb

Synthesis and 3D-QSAR study of 1,4-dihydropyridine derivatives as MDR cancer reverters

A series of symmetrical and unsymmetrical 1,4-dihydropyridines were synthesized by a rapid, single pot microwave irradiation (MWI) based protocol along with conventional approach and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their tumor cell cytotoxicity in HL-60 tumor cells. A 3D-QSAR study using CoMFA and CoMSIA was carried out to decipher the factors governing MDR reversing ability in cancer. The resulting contour maps derived by the best 3D-QSAR models provide a good insight into the molecular features relevant to the biological activity in this series of analogs. 3D contour maps as a result of 3D-QSAR were utilized to identify some novel features that can be incorporated into the 1,4-dihydropyridine framework to enhance the activity

Additional file 3: of A case of Raine syndrome presenting with facial dysmorphy and review of literature

Homology modeling, structure validation and protein stability due to c.1228T>A (p.Ser410Thr) variant. File describes the influence of variant change on the protein structure (DOCX 16 kb

Additional file 2: of A case of Raine syndrome presenting with facial dysmorphy and review of literature

Sanger sequencing (Variant Confirmation Test). It describes the details of primer’s used during Sanger sequencing of the proband and parents (DOCX 15 kb

Additional file 4: of A case of Raine syndrome presenting with facial dysmorphy and review of literature

Conservation of the FAM20C p.Ser410Thr residue in orthologs. Conservation of the variant in orthologs and Homo sapiens. (DOCX 15 kb

Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India

Abstract Background Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells’ lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20–40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality. Methods The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients’ initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula. Results The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887. Conclusions The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India