There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.

No abstract

Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. To date, 67 autosomal recessive nonsyndromic hearing impairment (ARNSHI) loci have been mapped, and 24 genes have been identified. This report describes three large consanguineous ARNSHI Pakistani families, all of which display linkage to marker loci located in the genetic interval of DFNB49 locus on chromosome 5q13. Recently, Riazuddin et al. (Am J Hum Genet 2006; 79:1040-1051 reported that variants within the TRIC gene, which encodes tricellulin, are responsible for HI due to DFNB49. TRIC gene sequencing in these three families led to the identification of a novel mutation (IVS4 + 1G [ A) in one family and the discovery of a previously described mutation (IVS4 + 2T [ C) in two families. It is estimated that 1.06% (95% confidence interval 0.02-3.06%) of families with ARNSHI in Pakistan manifest HI due to mutations in the TRIC gene.

Genetic polymorphisms in TAGAP gene have been associated with many diseases including rheumatoid arthritis, multiple sclerosis and other autoimmune disorders. Identifying functional SNPs in such disease associated genes is an uphill task hence before planning larger population study, it is better to scrutinize putative functional SNPs. In this study we used various computational approaches to identify nsSNPs which are deleterious to the structure and/or function of TAGAP protein that might be causing these diseases. Computational analysis was performed by five different in silico tools including SIFT, PROVEAN, PolyPhen-2, PhD-SNP and SNPs&GO. The study concludes that mutations of Glycine → Glutamic Acid at position 120, Glycine → Tryptophan at position 141 and Valine → Methionine at position 151 are major mutations in native TAGAP protein which might contribute to its malfunction and ultimately causing disease. The study also proposed 3D structures of native TAGAP protein and its three mutants. Future studies should consider these nsSNPs as main target mutations in various diseases involving TAGAP malfunction. This is the first comprehensive study, where TAGAP gene variants were analyzed using in silico tools hence will be of great help while considering large scale studies and also in developing precision medicines for cure of diseases related to these polymorphisms. Furthermore, animal models of various autoimmune diseases and having these mutations might be of help in exploring their precise roles.

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. It has been found to be associated with frontotemporal lobar degeneration (FTLD). In the present study, we have described homozygosity mapping and gene sequencing in a consanguineous autosomal recessive Pakistani family showing non-juvenile ALS without signs of FTLD. Gene mapping was carried out in all recruited family members using microsatellite markers, and linkage was established with sigma non-opioid intracellular receptor 1 (SIGMAR1) gene at chromosome 9p13.2. Gene sequencing of SIGMAR1 revealed a novel 3'-UTR nucleotide variation c.672*31A>G (rs4879809) segregating with disease in this family. The C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls. In silico analysis was carried out to explore the possible role of 3'-UTR variant of SIGMAR1 in ALS. The Regulatory RNA motif and Element Finder program revealed disturbance in miRNA (hsa-miR-1205) binding site due to this variation. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores due to this variation. Our results indicate that the 3'-UTR SIGMAR1 variant c.672*31A>G may have a role in the pathogenesis of ALS in this family.

Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ∼ 1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai-Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID.

MicroRNAs (miRNAs) are short 20-22 nucleotide non-coding RNA sequences. Recently identified, these are novel regulators of gene expression at translational level as well as transcriptional level. Alteration in miRNAs level has been observed in a number of human diseases and studies have been conducted on the effect of altered expression level of miRNAs on the development and progression of different diseases. The miRNAs can be used as molecular biomarkers in a number of diseases. Also, miRNAs are promising in providing a new platform for molecular therapeutics of previously incurable diseases. This review will focus on the introduction, recent advances in the field of miRNA and its importance in some human disorders.