Molecular insights into the role of genetic determinants of congenital hypothyroidism

In our previous studies, we have demonstrated the association of certain variants of the thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (TG) genes with congenital hypothyroidism. Herein, we explored the mechanistic basis for this association using different in silico tools. The mRNA 3'-untranslated region (3'-UTR) plays key roles in gene expression at the post-transcriptional level. In TSHR variants (rs2268477, rs7144481, and rs17630128), the binding affinity of microRNAs (miRs) (hsa-miR-154-5p, hsa-miR-376a-2-5p, hsa-miR-3935, hsa-miR-4280, and hsa-miR-6858-3p) to the 3'-UTR is disrupted, affecting post-transcriptional gene regulation. TPO and TG are the two key proteins necessary for the biosynthesis of thyroid hormones in the presence of iodide and H2O2. Reduced stability of these proteins leads to aberrant biosynthesis of thyroid hormones. Compared to the wild-type TPO protein, the p.S398T variant was found to exhibit less stability and significant rearrangements of intra-atomic bonds affecting the stoichiometry and substrate binding (binding energies, ΔG of wild-type vs. mutant: ‒15 vs. ‒13.8 kcal/mol; and dissociation constant, Kd of wild-type vs. mutant: 7.2E-12 vs. 7.0E-11 M). The missense mutations p.G653D and p.R1999W on the TG protein showed altered ΔG (0.24 kcal/mol and 0.79 kcal/mol, respectively). In conclusion, an in silico analysis of TSHR genetic variants in the 3'-UTR showed that they alter the binding affinities of different miRs. The TPO protein structure and mutant protein complex (p.S398T) are less stable, with potentially deleterious effects. A structural and energy analysis showed that TG mutations (p.G653D and p.R1999W) reduce the stability of the TG protein and affect its structure-functional relationship.

Mutational pressure drives evolution of synonymous codon usage in genetically distinct oenothera plastomes

Most of the amino acids are encoded by more than one codon, termed as synonymous codons. Synonymous codon usage is not random as it is unique to species. In each amino acid family, some synonymous codons are preferred and this is referred to as synonymous codon usage bias [SCUB]. Trends associated with evolution of SCUB and factors influencing its diversification in plastomes of genetically distinct Oenothera plastomes have not been investigated so far. In the present study, major forces that shape SCUB in Oenothera plastomes and putative preferred codons in the protein coding genes [PCG] of plastomes were identified. To unravel various features of SCUB across selected Oenothera plastomes, commonly used codon usage indices such as relative synonymous codon usage [RSCU], synonymous codon usage order [SCUO], effective number of codons [ENC] and codon adaptation index [CAI] were calculated. Correspondence analysis [COA] on RSCU was performed to identify various characteristics of SCUB across different PCG in Oenothera plastomes. Spearman's rank correlation analysis was adopted to correlate nucleotide contents, codon usage indices and major axes of COA to find out critical parameters in shaping SCUB. Mutational bias due to compositional constraints played crucial role in shaping SCUB as T[3] and GC[3] contents were in strong negative correlation with all axes of COA. Nevertheless, significant negative correlations between axis 1 and 3 with ENC and CAI respectively, in all species, and narrow distribution of GC contents in neutrality plot, indicate the role of natural selection. Hydropathy score of proteins was found to be influencing SCUB in O. glazioviana as it showed strong negative correlation with axis 2. We concluded that mutational pressure coupled with weak selection influenced SCUB in the examined plastomes of Oenothera. In addition, all examined species of Oenothera exist as disjunct populations in different parts of North America and these populations might have experienced genetic drift as random mutations in small populations that have been fixed over a period of time

A Primary Care Approach to Myelodysplastic Syndromes / 가정의학회지

Myelodysplastic syndromes (MDS) are probably the most common hematologic malignancies in adults over the age of 60 and are a major source of morbidity and mortality among older age groups. Diagnosis and management of this chronic blood cancer has evolved significantly in recent years and there are Food and Drug Administration-approved therapies that can extend patients' life expectancy and improve quality of life. Primary care physicians (PCPs) are often involved in the process of diagnosis and follow-up of MDS patients, especially those in low-risk groups. They can therefore play an important role in improving patient care and quality of life by ensuring early referral and participating in supportive management. There is also a shortage of oncologists which increases the importance of the role of PCPs in management of MDS patients. In the face of limited resources, PCPs can improve access and quality of care in MDS patients. This article provides an overview of the common manifestations, diagnostic approaches, and therapeutic modalities of MDS for PCPs, with a focus on when to suspect MDS, when a referral is appropriate, and how to provide appropriate supportive care for patients diagnosed with MDS.

Identification of 1,531 cSNPs from Full-length Enriched cDNA Libraries of the Korean Native Pig Using in Silico Analysis

Sequences from the clones of full-length enriched cDNA libraries serve as valuable resources for functional genomics related studies, genome annotation and SNP discovery. We analyzed 7,392 high-quality chromatograms (Phred value >30) obtained from sequencing the 5' ends of clones derived from full-length enriched cDNA libraries of Korean native pigs including brainstem, liver, cerebellum, neocortex and spleen libraries. In addition, 50,000 EST sequence trace files obtained from GenBank were combined with our sequences to identify cSNPs in silico. The process generated 11,324 contigs, of which 2,895 contigs contained at least one SNP and among them 610 contigs had a minimum of one sequence from Korean native pigs. Of 610 contigs, we randomly selected 262 contigs and performed in silico analysis for the identification of cSNPs. From the results, we identified 1,531 putative coding single nucleotide polymorphisms (cSNPs) and the SNP detection frequency was one SNP per 465 bp. A large-scale sequencing result of clones from full-length enriched cDNA libraries and identified cSNPs will serve as a useful resource to functional genomics related projects such as a pig HapMap project in the near future

Genetics of deafness in India.

Linkage analysis in families with hereditary hearing loss have revealed a plethora of chromosomal locations linked to deafness reflecting the extreme heterogeneity of the disorder. 40 of the genes contained within these loci have been mapped lending an insight into the diverse molecules operating in the inner ear and the remarkable complexity of the cellular and molecular processes involved in the transucdation of sound in the auditory system. Among this diversity, Connexin 26 has been found to be the most common cause of deafness the world around. The authors review here the prevalence of this gene in the Indian population as found in their study, together with other deafness genes segregating non-syndromic deafness, accounting for approximately 40% of all cases. This indicates there are several more to be identified yet. Knowledge of the genetic cause of deafness in our families is important for accurate genetic counseling and early diagnosis for timely intervention and treatment options.

Fine needle aspiration cytology of extrapancreatic solid-cystic tumour of pancreas: a case report.

Fine needle aspiration cytological features of solid-cystic tumor (SCT) of pancreas occurring adjacent to pancreas is reported for its rare occurrence. On cytology, diagnosis of paraganglioma was suggested. After histologic diagnosis of SCT, cytology was reviewed that showed typical features of SCT. On cytology, diagnostic problem in SCT occurring outside pancreas is illustrated.

Prenatal diagnosis of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is one of the most common X-linked genetic disorders seen in children. Mutations in the DMD gene coding for the protein dystrophin causes the severe muscle-wasting disorder leading to death in the second decade of life. In the absence of a cure, prenatal diagnosis (PND) appears to be the best approach to reduce the burden of this disease on the individual family and ultimately on society. There are few published reports worldwide on PND and very few from the developing countries. We report our experience with PND for families with DMD using multiplex polymerase chain reaction (PCR) and microsatellite polymorphic marker analysis. METHODS: From August 1997 to October 1999, PND was offered on request to 23 families with one or two boys affected with DMD. A total of 26 foetuses were screened for DMD. Initially the deletions in the DMD gene in the affected child were identified by multiplex PCR screening for 23 exons in 6 sets. In patients where deletions were not identified, microsatellite repeat analysis was carried out to follow the inheritance of the mutant allele. DNA was extracted from chorionic villus samples obtained by chorionic villus biopsy performed at 10-15 weeks of gestation in 17 families, and at 16-20 weeks in 6 families. RESULTS: Deletions were identified in 20 affected boys. In 2 families, microsatellite repeat analysis was done to identify the mutant allele. Of the 26 foetuses, 5 were found to be affected with DMD and the parents opted for termination of pregnancies. CONCLUSIONS: Multiplex PCR technology and microsatellite repeat analysis can be used effectively for PND of DMD.