Publications by authors named "John B Vincent"

184 Publications

Homozygosity mapping coupled with whole-exome sequencing and protein modelling identified a novel missense mutation in in a consanguineous Pakistani family with Leber congenital amaurosis.

J Genet 2021 ;100

Institute of Biological Sciences, Gomal University, D.I.Khan 29050, Khyber Pakhtunkhwa, Pakistan

Leber congenital amaurosis (LCA) is a rare form of early onset vision loss or blindness due to retinal dystrophy. This condition is characterized by early vision loss, nystagmus and severe retinal dysfunction. To date, genetic studies have reported 19 genes to be associated with autosomal recessive LCA, most of which are involved in the retinal morphology and the physiology of the phototransduction pathway. In the current study, a large consanguineous family segregating congenital blindness was ascertained from the Dera Ismail Khan region of Pakistan. Genetic analysis was performed through genomewide SNP genotyping (for homozygosity-by-descent mapping), whole-exome sequencing (for mutation identification) and Sanger sequencing (for segregation analysis). structural predictions were performed through SWISS-Model (structure prediction) and ClusPro (molecular docking). Molecular investigation of the present LCA family identified a novel homozygous missense mutation p.Asp306Val in gene (NM_000180.3:c.917A>T). In silico structural modelling and interaction studies predicted significant changes in protein folding and interacting residues. The present molecular genetic study further extends the mutational spectrum of in LCA, and its genetic heterogeneity in the Pakistani population. The findings of the computational studies on protein structure and interaction profile predicted pathogenic consequences of p.Asp306Val on GUCY2D function.
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January 2021

Exome sequencing identifies novel and known mutations in families with intellectual disability.

BMC Med Genomics 2021 Aug 27;14(1):211. Epub 2021 Aug 27.

Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan.

Background: Intellectual disability (ID) is a phenotypically and genetically heterogeneous disorder.

Methods: In this study, genome wide SNP microarray and whole exome sequencing are used for the variant identification in eight Pakistani families with ID. Beside ID, most of the affected individuals had speech delay, facial dysmorphism and impaired cognitive abilities. Repetitive behavior was observed in MRID143, while seizures were reported in affected individuals belonging to MRID137 and MRID175.

Results: In two families (MRID137b and MRID175), we identified variants in the genes CCS and ELFN1, which have not previously been reported to cause ID. In four families, variants were identified in ARX, C5orf42, GNE and METTL4. A copy number variation (CNV) was identified in IL1RAPL1 gene in MRID165.

Conclusion: These findings expand the existing knowledge of variants and genes implicated in autosomal recessive and X linked ID.
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http://dx.doi.org/10.1186/s12920-021-01066-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399827PMC
August 2021

Low-molecular-weight chromium-binding substance (LMWCr) may bind and carry Cr(III) from the endosome.

J Inorg Biochem 2021 Oct 22;223:111555. Epub 2021 Jul 22.

Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Electronic address:

Trivalent chromium has been proposed to be transported in vivo from the bloodstream to the tissues via endocytosis by transferrin (Tf), the major iron transport protein in the blood. While Cr(III) loss from the Tf/Tf receptor complex after acidification to pH 5.5 has recently been shown to be sufficiently rapid to be physiologically relevant, the released Cr(III) still must exit the endosome during the time of the endocytosis cycle (circa 15 min). Cr(III) binds too slowly to small ligands such as citrate or ascorbate, or even EDTA, for such complexes to form and be transported from the endosome, while no trivalent ion transporters are known. However, the apo form of the peptide low-molecular-weight chromium-binding substance (LMWCr) can remove Cr(III) from Cr(III)-Tf at neutral pH, albeit slowly, and LMWCr is known to be transported from cells after binding Cr(III), although the transporter is not known. LMWCr subsequently carries Cr(III) to the bloodstream ultimately for removal from the body in the urine. The rate of binding of Cr(III) to apoLMWCr was significantly enhanced in the presence of the Tf/Tf receptor complex. These results suggest that apoLMWCr may function to bind Cr(III) released in the endosomes for ultimate removal from the body as part of a Cr(III) detoxification process.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111555DOI Listing
October 2021

Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features.

Eur J Hum Genet 2021 Aug 24;29(8):1226-1234. Epub 2021 Jun 24.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, London, UK.

The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outlin`e the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.
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http://dx.doi.org/10.1038/s41431-021-00910-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385073PMC
August 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Examining the Potential Formation of Ternary Chromium-Histidine-DNA Complexes and Implications for Their Carcinogenicity.

Biol Trace Elem Res 2021 May 4. Epub 2021 May 4.

Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, AL, 35487-0336, USA.

The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories efforts to establish the structure and properties of discrete binary and ternary adducts of Cr(III) and DNA at a molecular level, the properties of Cr(III)-histidine-DNA complexes formed from Cr(III) were examined. These studies determined the composition of previously described "prereacted" chromium histidinate and reveal the reaction of "prereacted" chromium histidinate with DNA does not form ternary complexes as previously proposed. The products instead are chromium histidinate complexes weakly bound, probably in the minor groove, to DNA. These weakly bound adducts cannot be responsible for the mutagenic and carcinogenic properties ascribed to ternary Cr(III)-histidine-DNA adducts. The results of biological studies where "ternary adducts" of Cr(III), histidine, and DNA were made from "prereacted" chromium histidinate must, therefore, be interpreted with caution.
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http://dx.doi.org/10.1007/s12011-021-02743-wDOI Listing
May 2021

Examining the Potential Formation of Ternary Chromium-Histidine-DNA Complexes and Implications for Their Carcinogenicity.

Biol Trace Elem Res 2021 May 4. Epub 2021 May 4.

Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, AL, 35487-0336, USA.

The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories efforts to establish the structure and properties of discrete binary and ternary adducts of Cr(III) and DNA at a molecular level, the properties of Cr(III)-histidine-DNA complexes formed from Cr(III) were examined. These studies determined the composition of previously described "prereacted" chromium histidinate and reveal the reaction of "prereacted" chromium histidinate with DNA does not form ternary complexes as previously proposed. The products instead are chromium histidinate complexes weakly bound, probably in the minor groove, to DNA. These weakly bound adducts cannot be responsible for the mutagenic and carcinogenic properties ascribed to ternary Cr(III)-histidine-DNA adducts. The results of biological studies where "ternary adducts" of Cr(III), histidine, and DNA were made from "prereacted" chromium histidinate must, therefore, be interpreted with caution.
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http://dx.doi.org/10.1007/s12011-021-02743-wDOI Listing
May 2021

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics.

Front Genet 2021 21;12:620859. Epub 2021 Jan 21.

Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.

Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.
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http://dx.doi.org/10.3389/fgene.2021.620859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859524PMC
January 2021

MeCP2: latest insights fundamentally change our understanding of its interactions with chromatin and its functional attributes.

Bioessays 2021 03 8;43(3):e2000281. Epub 2021 Jan 8.

Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.

Methyl CpG binding protein 2 (MeCP2) was initially isolated as an exclusive reader of DNA methylated at CpG. This recognition site, was subsequently extended to other DNA methylated residues and it has been the persisting dogma that binding to methylated DNA constitutes its physiologically relevant role. As we review here, two very recent papers fundamentally change our understanding of the interactions of this protein with chromatin, as well as its functional attributes. In the first one, the protein has been shown to bind to tri-methylated histone H3 (H3K27me3), providing a hint for what might turn out to be the first described chromodomain-containing protein reader in the animal kingdom, and unequivocally demonstrates the ability of MeCP2 to bind to nonmethylated CpG regions of the genome. The second paper reports how the protein dynamically participates in the formation of constitutive heterochromatin condensates. Histone H3K27me3 is a critical component of this form of chromatin.
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http://dx.doi.org/10.1002/bies.202000281DOI Listing
March 2021

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability.

Transl Psychiatry 2021 01 5;11(1). Epub 2021 Jan 5.

Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.

PIDD1 encodes p53-Induced Death Domain protein 1, which acts as a sensor surveilling centrosome numbers and p53 activity in mammalian cells. Early results also suggest a role in DNA damage response where PIDD1 may act as a cell-fate switch, through interaction with RIP1 and NEMO/IKKg, activating NF-κB signaling for survival, or as an apoptosis-inducing protein by activating caspase-2. Biallelic truncating mutations in CRADD-the protein bridging PIDD1 and caspase-2-have been reported in intellectual disability (ID), and in a form of lissencephaly. Here, we identified five families with ID from Iran, Pakistan, and India, with four different biallelic mutations in PIDD1, all disrupting the Death Domain (DD), through which PIDD1 interacts with CRADD or RIP1. Nonsense mutations Gln863* and Arg637* directly disrupt the DD, as does a missense mutation, Arg815Trp. A homozygous splice mutation in the fifth family is predicted to disrupt splicing upstream of the DD, as confirmed using an exon trap. In HEK293 cells, we show that both Gln863* and Arg815Trp mutants fail to co-localize with CRADD, leading to its aggregation and mis-localization, and fail to co-precipitate CRADD. Using genome-edited cell lines, we show that these three PIDD1 mutations all cause loss of PIDDosome function. Pidd1 null mice show decreased anxiety, but no motor abnormalities. Together this indicates that PIDD1 mutations in humans may cause ID (and possibly lissencephaly) either through gain of function or secondarily, due to altered scaffolding properties, while complete loss of PIDD1, as modeled in mice, may be well tolerated or is compensated for.
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http://dx.doi.org/10.1038/s41398-020-01158-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791037PMC
January 2021

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2020 10 28;52(10):1046-1056. Epub 2020 Sep 28.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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http://dx.doi.org/10.1038/s41588-020-0695-1DOI Listing
October 2020

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Am J Hum Genet 2020 08 31;107(2):311-324. Epub 2020 Jul 31.

Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413890PMC
August 2020

X-ray structure of chromium(III)-containing transferrin: First structure of a physiological Cr(III)-binding protein.

J Inorg Biochem 2020 09 23;210:111101. Epub 2020 May 23.

Department of Chemistry & Biochemistry, The University of Alabama, 250 Hackberry Lane, Tuscaloosa, AL 35487-0336, USA. Electronic address:

Transferrin, the Fe(III) transport protein in mammalian blood, has been suggested to also serve as a Cr(III) transporter and as part of a Cr(III) detoxification system; however, the structure of the metal-binding sites has never been fully elucidated with bound Cr(III). Chromium(III)-transferrin was crystallized in the presence of the synergistic anion malonate. In the crystals, the protein exists with a closed C-terminal lobe containing a Cr(III) ion and an open, unoccupied N-terminal lobe. The overall structure and the metal ion environments are extremely similar to those of Fe(III)- and Ti(IV)-containing transferrin crystallized under comparable conditions. The octahedral coordination about the Cr(III) is comprised of four ligands provided by the protein (two tyrosine residues, a histidine residue, and an aspartate residue) and a chelating malonate anion. This represents the first crystal structure of a Cr(III)-containing protein that binds Cr(III) as part of its physiological function.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111101DOI Listing
September 2020

Intraspecific trait variation across elevation predicts a widespread tree species' climate niche and range limits.

Ecol Evol 2020 May 17;10(9):3856-3867. Epub 2020 Apr 17.

Department of Ecology and Evolutionary Biology University of Tennessee Knoxville TN USA.

Global change is widely altering environmental conditions which makes accurately predicting species range limits across natural landscapes critical for conservation and management decisions. If climate pressures along elevation gradients influence the distribution of phenotypic and genetic variation of plant functional traits, then such trait variation may be informative of the selective mechanisms and adaptations that help define climatic niche limits. Using extensive field surveys along 16 elevation transects and a large common garden experiment, we tested whether functional trait variation could predict the climatic niche of a widespread tree species () with a double quantile regression approach. We show that intraspecific variation in plant size, growth, and leaf morphology corresponds with the species' total climate range and certain climatic limits related to temperature and moisture extremes. Moreover, we find evidence of genetic clines and phenotypic plasticity at environmental boundaries, which we use to create geographic predictions of trait variation and maximum values due to climatic constraints across the western US. Overall, our findings show the utility of double quantile regressions for connecting species distributions and climate gradients through trait-based mechanisms. We highlight how new approaches like ours that incorporate genetic variation in functional traits and their response to climate gradients will lead to a better understanding of plant distributions as well as identifying populations anticipated to be maladapted to future environments.
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http://dx.doi.org/10.1002/ece3.5969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244802PMC
May 2020

Effects of Bitter Melon and a Chromium Propionate Complex on Symptoms of Insulin Resistance and Type 2 Diabetes in Rat Models.

Biol Trace Elem Res 2021 Mar 2;199(3):1013-1026. Epub 2020 Jun 2.

Institute of Human Nutrition and Dietetics, The Poznań University of Life Sciences, Wojska Polskiego 31, 60-624, Poznań, Poland.

Trivalent chromium (Cr) and bitter melon (Momordica charantia L., BM) have been shown to independently interact with the insulin signaling pathway leading to improvements in the symptoms of insulin resistance and diabetes in some animal models and human subjects. The aim of this study was to examine whether the combination of the two nutritional supplements could potentially have additive effects on treating these conditions in high-fat-fed streptozotocin (STZ)-induced diabetic rats. The experiment was conducted with 110 male Wistar rats divided into eleven groups and fed either a control or high-fat diet for 7 weeks. Half of the rats on the high-fat diet were injected with STZ (30 mg/kg body mass) to induce diabetes. The high-fat (HF) diets were then supplemented with a combination of Cr (as chromium(III) propionate complex, Cr3: either 10 or 50 mg Cr/kg diet) and bitter melon (lyophilized whole fruit: either 10 or 50 g/kg diet) for 6 weeks. After termination of the experiment, blood and internal organs were harvested for blood biochemical, hematological, and mineral (Cr) analyses using appropriate analytical methods. It was found that neither Cr(III) nor BM was able to significantly affect blood indices in HF and diabetic rats, but BM tended to improve body mass gain, blood glucose, and LDL cholesterol values, but decreased Cr content in the liver and kidneys of the Cr-co-supplemented type 2 diabetic model of rats. Supplementary Cr(III) had no appreciable effect on glucose and lipid metabolism in high-fat-fed STZ-induced diabetic rats. Supplementary BM fruit powder had some observable effects on body mass of high-fat-fed rats; these effects seem to be dampened when BM was co-administered with Cr. Cr(III) and BM appear to act as nutritional antagonists when both administered in food, probably due to binding of Cr by the polyphenol-type compounds present in the plant material. Graphical Abstract.
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http://dx.doi.org/10.1007/s12011-020-02202-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813737PMC
March 2021

A novel biallelic single base insertion in WNK1 in a Pakistani family with congenital insensitivity to pain.

J Hum Genet 2020 May 3;65(5):493-496. Epub 2020 Mar 3.

Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare, recessively inherited neurological condition frequently involving insensitivity to pain. The subtype, HSAN2A, results from mutations in the gene WNK1. We identified a consanguineous Pakistani family with three affecteds showing symptoms of HSANII. We performed microarray genotyping, followed by homozygosity-by-descent (HBD) mapping, which indicated several significant HBD regions, including ~6 Mb towards the terminus of chromosome 12p, spanning WNK1. Simultaneously, we performed whole exome sequencing (WES) on one of the affected brothers, and identified a homozygous 1 bp insertion variant, Chr12:978101dupA, within exon 10. This variant, confirmed to segregate in the family, is predicted to truncate the protein (NM_213655.4:c.3464delinsAC; p.(Thr1155Asnfs*11) and lead to nonsense-mediated mRNA decay of the transcript. Previous studies of congenital pain insensitivity/HSANII in Pakistani families have identified mutations in SCN9A. Our study identified a previously unreported WNK1 mutation segregating with congenital pain insensitivity/HSANII in a Pakistani family.
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http://dx.doi.org/10.1038/s10038-020-0734-xDOI Listing
May 2020

Significance of conformation changes during the binding and release of chromium(III) from human serum transferrin.

J Inorg Biochem 2020 05 15;206:111040. Epub 2020 Feb 15.

Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Electronic address:

Trivalent chromium has been proposed to be transported in vivo from the bloodstream to the tissues via endocytosis by transferrin (Tf), the major iron transport protein in the blood. While both Cr(III) binding and release from Tf have been proposed to be too slow to be physiologically relevant, recent kinetic studies under physiological conditions demonstrate that Cr(III) binding and release are sufficiently fast to occur during the time of the endocytosis cycle (circa 15 min). Consequently, the release of Cr(III) from human and bovine serum Tf has been examined under conditions mimicking an endosome during endocytosis. These studies have also found that Cr(III)-Tf can exist in multiple conformations giving rise to different spectroscopic properties and different rates of Cr(III) release. Time-dependent spectroscopic studies of the binding and release of Cr(III) from human serum Tf have been used to identify three different conformations of Cr(III)-Tf. The conformation of Cr(III)-Tf used in most previous studies forms too slowly to be physiologically relevant and slowly releases Cr(III) in endosomal pH range. The conformation formed between 5 min to 60 min after the addition of Cr(III) to apoTf at pH 7.4 in 25 mM bicarbonate resembles the conformation of Cr(III)-Tf in its complex with Tf receptor (TfR) and loses Cr(III) rapidly at endosomal pH, although not as fast as the Tf-TfR complex. The significance of these conformations and the potential role of Tf in detoxification of Cr(III) are described.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108967PMC
May 2020

Mechanistic Study of Enhanced Protonation by Chromium(III) in Electrospray Ionization: A Superacid Bound to a Peptide.

J Am Soc Mass Spectrom 2020 Feb 31;31(2):308-318. Epub 2019 Dec 31.

Department of Chemistry & Biochemistry , The University of Alabama , Tuscaloosa , Alabama 35487-0336 , United States.

Addition of trivalent chromium, Cr(III), to solutions undergoing electrospray ionization (ESI) enhances protonation and leads to formation of [M + 2H] for peptides that normally produce [M + H]. This effect is explored using electronic structure calculations at the density functional theory (DFT) level to predict the energetics of various species that are potentially important to the mechanism. Gas- and solution-phase reaction free energies for glycine and its anion reacting with [Cr(III)(HO)] and for dehydration of these species have been predicted, where glycine is used as a simple model for a peptide. For comparison, calculations were also performed with Fe(III), Al(III), Sc(III), Y(III), and La(III). Removal of water from these complexes, as would occur during the ESI desolvation process, results in species that are highly acidic. The calculated p of Cr(III) with a single solvation shell is -10.8, making [Cr(III)(HO)] a superacid that is more acidic than sulfuric acid (p = -8.8). Binding to glycine requires removal of two aqua ligands, which gives [Cr(III)(HO)] that has an extremely acidic p of -28.8. Removal of additional water further enhances acidity, reaching a p of -84.7 for [Cr(III)(HO)]. A mechanism for enhanced protonation is proposed that incorporates computational and experiment results, as well as information on the known chemistry of Cr(III), which is substitutionally inert. The initial step involves binding of [Cr(III)(HO)] to the deprotonated C-terminus of a peptide. As the drying process during ESI strips water from the complex, the resulting superacid transfers protons to the bound peptide, eventually leading to formation of [M + 2H].
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http://dx.doi.org/10.1021/jasms.9b00078DOI Listing
February 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

Release of trivalent chromium from serum transferrin is sufficiently rapid to be physiologically relevant.

J Inorg Biochem 2020 01 20;202:110901. Epub 2019 Oct 20.

Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Electronic address:

Transferrin, the major iron transport protein in the blood, apparently also transports trivalent chromium in vivo via endocytosis. Recent in vitro studies have, however, suggested that the release of chromic ions from serum transferrin is too slow to be biologically relevant. Consequently, the release of chromium(III) from human serum transferrin has been examined under conditions mimicking an endosome during endocytosis. At pH 4.5 and 5.5, the release of Cr(III) from transferrin occurs rapidly from the weak binding site. While appreciably slower, the release of Cr(III) from the tighter site in the presence of biological chelating agents is potentially sufficiently fast to be physiologically relevant. When Cr(III)-loaded transferrin is added to soluble transferrin receptor, the interaction with the receptor results in Cr(III) in both the weak and tight binding sites giving rise to an EPR signal similar to that of the weak binding site; concurrently, the loss of Cr(III) from both binding sites becomes rapid at acidic pH, more rapid than from either site in the absence of the receptor. Loss of Cr(III) from the transferrin-transferrin receptor complex, thus, is easily sufficiently rapid for transferrin to serve as the physiological transporter of Cr(III) from the bloodstream to the tissues. However, detailed studies of conformational changes of transferrin associated with the binding and release of chromium along with investigations of how and at what rate Cr(III) is transported from the endosome will be required before this question of whether transferrin transport Cr(III) in vivo can be definitively resolved.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110901DOI Listing
January 2020

MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.

Epigenetics Chromatin 2019 10 10;12(1):63. Epub 2019 Oct 10.

Department of Biochemistry and Microbiology, University of Victoria, Petch Building 260, Victoria, BC, V8W 3P6, Canada.

Background: MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.

Results: Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.

Conclusions: Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
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http://dx.doi.org/10.1186/s13072-019-0298-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786283PMC
October 2019

Effects of chromium supplementation on body composition, human and animal health, and insulin and glucose metabolism.

Authors:
John B Vincent

Curr Opin Clin Nutr Metab Care 2019 11;22(6):483-489

Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama.

Purpose Of Review: Chromium(III) has been proposed to have a nutritional or pharmacological role in changing body composition and improving symptoms of insulin resistance, type 2 diabetes, and related conditions although the mode of action of Cr(III) at a molecular level has failed to be elucidated. This review details the current status of studies into Cr(III) supplementation.

Recent Findings: Clinical trials, meta-analyses and systematic reviews have failed to demonstrate clinically significant effects from Cr(III) supplementation on body composition or symptoms of insulin resistance and related conditions in humans and farm animals. Although new Cr(III) supplements continue to appear in the scientific literature, studies have failed to elucidate the mechanism of chromium action at a molecular level. Conflicting results on a role of transferrin in Cr(III) transport and detoxification have appeared.

Summary: Cr(III) supplementation cannot currently be recommended in humans or farm animals. Further studies are required to probe the mechanism of Cr(III) action in increasing insulin sensitivity and glucose uptake in rodent models of insulin resistance and diabetes, with particular attention being turned to a potential role of transferrin in Cr(III) transport and detoxification.
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http://dx.doi.org/10.1097/MCO.0000000000000604DOI Listing
November 2019

Molecular Structure of Binary Chromium(III)-DNA Adducts.

Chembiochem 2020 03 15;21(5):628-631. Epub 2019 Oct 15.

The University of Alabama, Department of Chemistry and Biochemistry, Box 870336, 250 Hackberry Lane, Tuscaloosa, AL, 43587-0336, USA.

Chromium(VI) is a carcinogen and mutagen, and its mechanisms of action are proposed to involve binding of its reduction product, chromium(III), to DNA. The manner in which chromium(III) binds DNA has not been established, particularly at a molecular level. Analysis of oligonucleotide duplex DNAs by NMR, EPR, and IR spectroscopies in the presence of chromium(III) allows the elucidation of the Cr binding site. The metal centers were found to interact exclusively with guanine N7 positions. No evidence of chromium interactions with other bases or backbone phosphates nor of Cr forming intra-strand crosslinks between neighboring guanine residues was observed.
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http://dx.doi.org/10.1002/cbic.201900436DOI Listing
March 2020

GPT2 mutations in autosomal recessive developmental disability: extending the clinical phenotype and population prevalence estimates.

Hum Genet 2019 Oct 30;138(10):1183-1200. Epub 2019 Aug 30.

Developmental Disorders Genetics Research Program, Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University and Emma Pendleton Bradley Hospital, East Providence, RI, USA.

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.
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http://dx.doi.org/10.1007/s00439-019-02057-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748651PMC
October 2019

Association of smoked cannabis with treatment resistance in schizophrenia.

Psychiatry Res 2019 08 18;278:242-247. Epub 2019 Jun 18.

Department of Psychiatry, Queen's University, Kingston, ON, Canada. Electronic address:

Association of cannabis use with schizophrenia is a well-established finding. Its role in causation, however, is debated. Different studies have found that cannabis use impacts the outcome of schizophrenia and is associated with treatment non-adherence and a higher rate of relapses. In this paper, we investigated the impact of self-reported cannabis use on treatment response in a cohort of schizophrenia patients from Pakistan, a middle-income country. The data was collected from a psychiatric hospital in Khyber Pakhtunkhwa province of Pakistan where cannabis use is prevalent. Clinical evaluation and therapeutic response were established using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions Scales-Severity (CGI-S) and Improvement (CGI-I) scale. Lack of response to adequate treatment with two trials of antipsychotics was classed as treatment resistance. We compared the treatment-resistant and treatment responsive groups for different variables including cannabis use, age at onset of illness, duration of untreated psychosis and consanguinity. We had data on 230 patients. More than ninety percent of our participants were men. The rate of treatment resistance was over 60%. Ongoing use of cannabis had an association with treatment resistance. We only included cases where treatment adherence was not a problem.
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http://dx.doi.org/10.1016/j.psychres.2019.06.023DOI Listing
August 2019

Association of smoked cannabis with treatment resistance in schizophrenia.

Psychiatry Res 2019 08 18;278:242-247. Epub 2019 Jun 18.

Department of Psychiatry, Queen's University, Kingston, ON, Canada. Electronic address:

Association of cannabis use with schizophrenia is a well-established finding. Its role in causation, however, is debated. Different studies have found that cannabis use impacts the outcome of schizophrenia and is associated with treatment non-adherence and a higher rate of relapses. In this paper, we investigated the impact of self-reported cannabis use on treatment response in a cohort of schizophrenia patients from Pakistan, a middle-income country. The data was collected from a psychiatric hospital in Khyber Pakhtunkhwa province of Pakistan where cannabis use is prevalent. Clinical evaluation and therapeutic response were established using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions Scales-Severity (CGI-S) and Improvement (CGI-I) scale. Lack of response to adequate treatment with two trials of antipsychotics was classed as treatment resistance. We compared the treatment-resistant and treatment responsive groups for different variables including cannabis use, age at onset of illness, duration of untreated psychosis and consanguinity. We had data on 230 patients. More than ninety percent of our participants were men. The rate of treatment resistance was over 60%. Ongoing use of cannabis had an association with treatment resistance. We only included cases where treatment adherence was not a problem.
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http://dx.doi.org/10.1016/j.psychres.2019.06.023DOI Listing
August 2019

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Nat Genet 2019 05 1;51(5):793-803. Epub 2019 May 1.

Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
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http://dx.doi.org/10.1038/s41588-019-0397-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956732PMC
May 2019

Genetic studies of multiple consanguineous Pakistani families segregating oculocutaneous albinism identified novel and reported mutations.

Ann Hum Genet 2019 07 13;83(4):278-284. Epub 2019 Mar 13.

Gomal Centre of Biochemistry and Biotechnology, Gomal University, D.I. Khan, Pakistan.

Oculocutaneous albinism (OCA) is an autosomal-recessive disorder of a defective melanin pathway. The condition is characterized by hypopigmentation of hair, dermis, and ocular tissue. Genetic studies have reported seven nonsyndromic OCA genes, among which Pakistani OCA families mostly segregate TYR and OCA2 gene mutations. Here in the present study, we investigate the genetic factors of eight consanguineous OCA families from Pakistan. Genetic analysis was performed through single-nucleotide polymorphism (SNP) genotyping (for homozygosity mapping), whole exome sequencing (for mutation identification), Sanger sequencing (for validation and segregation analysis), and quantitative PCR (qPCR) (for copy number variant [CNV] validation). Genetic mapping in one family identified a novel homozygous deletion mutation of the entire TYRP1 gene, and a novel deletion of exon 19 in the OCA2 gene in two apparently unrelated families. In three further families, we identified homozygous mutations in TYR (NM_000372.4:c.1424G > A; p.Trp475*), NM_000372.4:c.895C > T; p.Arg299Cys), and SLC45A2 (NM_016180:c.1532C > T; p.Ala511Val). For the remaining two families, G and H, compound heterozygous TYR variants NM_000372.4:c.1037-7T > A, NM_000372.4:c.1255G > A (p.Gly419Arg), and NM_000372.4:c.1255G > A (p.Gly419Arg) and novel variant NM_000372.4:c.248T > G; (p.Val83Gly), respectively, were found. Our study further extends the evidence of TYR and OCA2 as genetic mutation hot spots in Pakistani families. Genetic screening of additional OCA cases may also contribute toward the development of Pakistani specific molecular diagnostic tests, genetic counseling, and personalized healthcare.
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http://dx.doi.org/10.1111/ahg.12307DOI Listing
July 2019
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