To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.
A combination of homozygosity mapping and exome sequencing was used ...to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California–San Francisco Chimera software.
All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.
LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.
AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino ...acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.
Polyhydroxyalkanoates (PHA) production and extraction of different bacterial strains isolated from contaminated urban and hilly areas was conducted. The 30 bacteria isolates were Gram negative and ...belonged to Pseudomonas, Citrobacter Klebsiella, Escherichia and Enterobacter genera. Bacterial level of resistance against antibiotics (Penicillin) and heavy metals (zinc, cadmium and copper) was determined. Bacterial isolates from contaminated urban areas were found to be more resistant. The screening for PHA production was done by the Sudan black staining. Among the urban area isolates, U17, U8 and U9 produced highest concentration of PHA (50.4, 40.6 and 37.9%) while in hilly area isolates H8, H6 and H9 showed highest production (45.8, 42.4 and 37.6%) by SDS digestion method. The percentage production was lowered when the extraction was done by sodium hypochlorite digestion method. Selected bacterial strains were optimized for PHA production at different growth conditions that is, pH, temperature and carbor sources. Bacterial isolates U8, U17 and H8 produced maximum amount of PHA 74 69 and 59%, respectively, at pH 7, 37C and using cooking oil as carbon source after 72 h. PHA polymerase phaC1/C2 genes were successfully amplified from genomic DNA of three bacterial isolates showing 540 bp DNA fragment which confirmed the presence of phaC1/C2 gene presence. It showed that the corresponding bacterial isolates would have been able to synthesize medium chair length PHA.
Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing ...(ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes ...have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.
Congenital disorders of glycosylation (CDG) are a large group of recessive multisystem disorders caused by impaired protein or lipid glycosylation. The CDG-I subgroup is characterized by protein ...N-glycosylation defects originating in the endoplasmic reticulum. The genetic defect is known for 17 different CDG-I subtypes. Patients in the few reported DPAGT1-CDG families exhibit severe intellectual disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism and structural brain anomalies. In this study, we report a non-consanguineous family with two affected adults presenting with a relatively mild phenotype consisting of moderate ID, epilepsy, hypotonia, aggressive behavior and balance problems. Exome sequencing revealed a compound heterozygous missense mutation, c.85A>T (p.I29F) and c.503T>C (p.L168P), in the DPAGT1 gene. The affected amino acids are located in the first and fifth transmembrane domains of the protein. Isoelectric focusing and high-resolution mass spectrometry analyses of serum transferrin revealed glycosylation profiles that are consistent with a CDG-I defect. Our results show that the clinical spectrum of DPAGT1-CDG is much broader than appreciated so far.
Backgrounds and Aims Next generation sequencing (NGS) approaches have revolutionized the identification of mutations underlying genetic disorders. This technology is particularly useful for the ...identification of mutations in known and new genes for conditions with extensive genetic heterogeneity. In the present study we investigated a consanguineous Pakistani family with intellectual disability (ID). Methods Genotyping was carried out using 250k and 6k SNP microarrays in order to perform homozygosity mapping and copy number variation (CNV) analysis. Targeted NGS was performed to identify the genetic defect in this family. qPCR was performed to validate and confirm the NGS result. Results Homozygosity mapping positioned the causative defect on chromosome 2p25.3–p25.2. Subsequent targeted NGS revealed an intragenic deletion of five exons of the gene TPO. Conclusions NGS is a powerful method to uncover submicroscopic structural variations. This result demonstrates that an unbiased screening approach such as NGS can help to identify even unexpected disease-causing mutations.
is belonging to the small immobile gram-negative spore-lacking cocco-bacilli bacteria family that grows in an aerobic environment, it is known as a zoonosis infection named brucellosis. This study ...was designed to investigate serum values of IL-23 in patient with brucellosis and investigate its relationship with cases with failure to respond to conventional medical therapy. A total of 372 individuals were divided into 2 groups (n=186) as follows: Group A comprising 186 infected participants with
(7-80 years-old), these people had not received antibiotics for at least 6 months ago. Group B including the healthy participants. All the participants in both groups were in the same age range. 5 ml blood samples were obtained from the participants intravenously (without anticoagulation substance). The serum level of IL-23 was investigated by ELISA diagnostic kit. The recorded data showed that the levels of IL-23 in the serum samples obtained from group A (143.64 Pg/ml) significantly (
<0.001) increased compared with this value in group B (23.14 Pg/ml). Based on the recorded data in the forms completed by all the participants at the day 0 of the experiment, 44 out of 186 individuals in group A, had experienced Brucellosis attack 2-3 times in spite of receiving medical prescriptions. A hypothesis about the possible immune system disorders in these participants lead us to did the re-sampling following drug administration. Results illustrated failure to respond to conventional medical therapy in patients with low level of serum IL-23.
The present study evaluated the cardioprotective effect of astaxanthin (ASX) against isoproterenol (ISO) induced myocardial infarction in rats via the pathway of mitochondrial biogenesis as the ...possible molecular target of astaxanthin. The control group was injected with normal physiological saline subcutaneously for 2 days. The second group was injected with ISO at a dose of 85 mg/kg bwt subcutaneously for 2 days. The third, fourth and fifth groups were supplemented with ASX at doses of 10, 20, 30 mg/kg bwt, respectively daily by oral gavage for 21 days then injected with ISO dose of 85 mg/kg bwt subcutaneously for 2 successive days. Isoproterenol administration in rats elevated the activities of Creatine kinase‐MB (CK‐MB), aspartate transaminase (AST), lactate dehydrogenase (LDH), and other serum cardiac biomarkers Troponin‐I activities, oxidative stress biomarkers, malondialdehyde(MDA), Nuclear factor‐kappa B (NF‐KB), while it decreased Peroxisome proliferator‐activated receptor‐gamma coactivator (PGC‐1α), Nuclear factor erythroid‐2‐related factor 2 (Nfe212), mitochondrial transcriptional factor A (mt TFA), mitochondrial DNA copy number and glutathione system parameters. However, Astaxanthin decreased the activities of serum AST, LDH, CK‐MB, and Troponin I that elevated by ISO. In addition, it increased glutathione peroxidase and reductase activities, total glutathione and reduced GSH content, and GSH/GSSG ratio, mtDNA copy number, PGC‐1α expression and Tfam expression that improved mitochondrial biogenesis while it decreased GSSG and MDA contents and NF‐KB level in the cardiac tissues. This study indicated that astaxanthin relieved isoproterenol induced myocardial infarction via scavenging free radicals and reducing oxidative damage and apoptosis in cardiac tissue.
Astaxanthin (ASX) decreased ISO elevated activities of serum AST, LDH, CK‐MB, and Troponin I. ASX increased mtDNA copy number, PGC‐1α expression and Tfam expression while decreased GSSG and MDA contents and NF‐KB level in the cardiac tissues.
Display omitted
•Current work is one of its kind study suggesting a material that can be used to fabricate a device that can simultaneously store memory and energy.•Low cost sol–gel method is used to ...synthesize iron chromite nanocrystals by varying Fe/Cr ratio.•Spinel phase i.e. FeCr2O4 is observed at Fe/Cr ratios of 0.45, 0.6 and 0.65.•Magneto dielectric (MD) studies confirm positive MD constant at 0.45, 0.6 & 0.65 Fe/Cr ratios.•The galvanostatic charging/discharging behavior shows capacitive behavior of FeCr2O4 samples.•The electrochemical results suggest that synthesized nanocrystals have potential for energy storage system.
Spinel ferrites with remarkable electrochemical performance and magnetodielectric (MD) coupling are promising candidates for energy storage and spintronic devices. This study focuses on structural phases, dielectric and magnetic polarization along with magnetodielectric (MD) coupling and electrochemical response of Fe-Cr spinels. Low cost sol–gel method is used to synthesize iron chromite nanopowders. Iron to chromium (Fe/Cr) ratio is varied in the range of 0.2–0.65 (with interval of 0.05). XRD patterns confirm the formation of phase pure FeCr2O4 at Fe/Cr ratios of 0.45, 0.6 & 0.65. Amorphous behavior is observed at Fe/Cr ratios of 0.2, 0.25, 0.5 & 0.55. Mixed phases are observed at 0.3, 0.35 & 0.4 Fe/Cr ratios. Formation of pure spinel phase at Fe/Cr ratio of 0.45 results in high saturation magnetization of 9.2 emu/g. High grain boundary resistance (189.62kΩ) and high dielectric constant (∼83.38 at log f = 5.0) along with low tangent loss (0.00423 at log f = 5) are observed at Fe/Cr ratio of 0.45. Magneto dielectric studies confirm positive magneto dielectric constant (MDC) of synthesized nanopowders at 0.45, 0.6 & 0.65 Fe/Cr ratios. Cyclic voltammetry is performed at constant potential window. Oxidation/reduction process leads to the pseudo-capacitive response of the material. The cyclic voltammetry curves show specific capacitance of 156 Fg−1, 144 Fg−1 and 152 Fg−1 at scan rate of 25 mV/s at Fe/Cr ratios of 0.45, 0.6 & 0.65 of FeCr2O4 nanopowders, respectively. The galvanostatic charging/discharging behavior shows capacitive behavior of FeCr2O4 nanopowders. The electrochemical results suggest that synthesized nanopowders have potential for energy storage system.
PDF
