scholarly journals Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (POH)

Genetika ◽  
2019 ◽  
Vol 51 (1) ◽  
pp. 347-355
Author(s):  
Jelena Gvozdenovic-Jeremic ◽  
Ljiljana Mojovic
Keyword(s):  
Drug Repositioning ◽  
Genetic Disorder ◽  
Potential Candidate ◽  
Molecular Signaling ◽  
Mice Model ◽  
Connective Tissues ◽  
Ectopic Ossification ◽  
Gene Encoding ◽  
Ectopic Bone ◽  
Progressive Osseous Heteroplasia

Progressive osseous heteroplasia (POH) is an ultrarare genetic disease of progressive ectopic ossification caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase (Gs?). Extensive ossification of the deep connective tissues can result in ankylosis of affected joints and growth retardation of involved limbs. Inhibition of main molecular signaling, Hedgehog (Hh) pathway, by pharmacological methods may reduce the severity of ectopic bone formation in POH patients. Hh inhibitors currently used or known for other conditions may be potential candidate drugs for treating this debilitating disease. In this study, three potential Hedgehog pathway inhibitors such as arsenic trioxide, statin, and vitamin D and their combinations were tested on subcutaneous mesenchymal progenitor (SMP) cells of G?s f/f mice model for possible therapeutic application for POH. The combination of these three drugs at their significantly reduced concentrations retained anti-osteogenic activity in SMP cells with aberrant Hedgehog activity. In that light, we propose here a potential new approach of the drug combination in order to reduce potential toxicity, the side effect and increase success rate for Hh inhibitors drug repositioning.

scholarly journals Mild Progressive Osseous Heteroplasia Overlap Syndrome With PTH and TSH Resistance Appearing During Adolescence and Not Early Childhood

2021 ◽  
Author(s):  
Kayo Ozaki ◽  
Akari Mituboshi ◽  
Masashi Nagai ◽  
Atushi Nishiyama ◽  
Gen Nishimura ◽  
...  
Keyword(s):  
Early Childhood ◽  
Dna Analysis ◽  
Genetic Disorder ◽  
Overlap Syndrome ◽  
Heterozygous Mutation ◽  
Loading Test ◽  
Ectopic Ossification ◽  
Old Japanese ◽  
Inactivating Mutations ◽  
Progressive Osseous Heteroplasia

Abstract Purpose: Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS­-inactivating mutations are classified as “inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2.” This study reports a case of mild POH overlap syndrome to improve understanding of genotype–phenotype correlations.Methods: A 13-year-and-6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies.Results: He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation.Conclusion: We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

scholarly journals Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

2020 ◽  
Vol 21 (4) ◽  
pp. 1340 ◽  
Author(s):  
Riko Nishimura ◽  
Kenji Hata ◽  
Yoshifumi Takahata ◽  
Tomohiko Murakami ◽  
Eriko Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Genetic Disorder ◽  
Interleukin 1 ◽  
Genetic Diseases ◽  
Mtor Inhibitors ◽  
Joint Diseases ◽  
Ectopic Ossification ◽  
Parathyroid Hormone Related Protein

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

scholarly journals Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith–Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Nidia Moreno-Corona ◽  
Loïc Chentout ◽  
Lucie Poggi ◽  
Romane Thouenon ◽  
Cecile Masson ◽  
...  
Keyword(s):  
Viral Infections ◽  
Genetic Disorder ◽  
Pi3 Kinase ◽  
Pi3k Signaling ◽  
Gene Encoding ◽  
Regulatory Subunits ◽  
Neurodevelopmental Delay ◽  
Exon 11 ◽  
Complex Genetic Disorder ◽  
Splice Product

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith–Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.

scholarly journals Mitochondrial Dysfunction in EAE Mice Brains and Impact of HIF1-α Induction to Compensate Energy Loss

2020 ◽  
Vol 7 (4) ◽  
Author(s):  
Mahboobeh Mosavimehr ◽  
Seyed Alireza Mesbah-Namin
Keyword(s):  
Energy Loss ◽  
Mitochondrial Dysfunction ◽  
Demyelinating Disease ◽  
Specific Activity ◽  
Hypoxia Inducible Factor ◽  
Neuronal Loss ◽  
Negative Control ◽  
Potential Candidate ◽  
Mice Model ◽  
Control Groups

Background: Mitochondrial dysfunction may be involved in the process of degradation and death of gray matter cells of the central nervous system (CNS) in patients with multiple sclerosis (MS). MS is known as a chronic, progressive demyelinating disease of the CNS. Objectives: Experimental autoimmune encephalomyelitis (EAE) mouse model of MS is the best method for extracting data trend for diagnosing this disorder. The aim of this study was to evaluate the specific activity of the Cytochrome oxidase (COX), ATP, and hypoxia-inducible factor 1 alpha (HIF-1α) in brain tissues of the EAE mice model. Methods: Twenty-one female mice (C57BL/6) were used, 9 for inducing the EAE model and 6 for each of both negative and sham control groups. The specific activity of the COX, ATP, and HIF-1α levels were evaluated in the whole brain of all 3 mice groups. Results: According to the findings, specific COX activity and ATP levels were decreased significantly, which could be due to the mitochondrial dysfunction and neuronal loss in MS lesions, whereas HIF-1α levels increased significantly in the EAE mice group, compared to the sham and negative control groups. The significant increase of HIF-1α levels reinforces the hypothesis that the HIF-1α induction may provide prevention of neuronal death by compensating energy loss under hypoxia-like conditions in EAE mice brains. Conclusions: The results of this study suggest that HIF-1α induction may also be a potential target for controlling the progression of MS, or the development of HIF-1α inducing compounds could be a potential candidate for the management of this disease and provide a rationale to conduct further research in this area.

Identification and functional characterisation of a novel KCNJ2 mutation, Val302del, causing Andersen–Tawil syndrome

2015 ◽  
Vol 93 (7) ◽  
pp. 569-575 ◽  
Author(s):  
Balázs Ördög ◽  
Lidia Hategan ◽  
Mária Kovács ◽  
György Seprényi ◽  
Zsófia Kohajda ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Clinical Importance ◽  
Inhibitory Effect ◽  
Periodic Paralysis ◽  
Inward Rectification ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Functional Characterisation

Loss-of-function mutations of the KCNJ2 gene encoding for the inward rectifier potassium channel subunit Kir2.1 cause Andersen–Tawil Syndrome (ATS), a rare genetic disorder characterised by periodic paralysis, ventricular arrhythmias, and dysmorphic features. Clinical manifestations of the disease appear to vary greatly with the nature of mutation, therefore, functional characterisation of ATS-causing mutations is of clinical importance. In this study, we describe the identification and functional analysis of a novel KCNJ2 mutation, Val302del, identified in a patient with ATS. Heterologously expressed wild type (WT) and Val302del mutant alleles showed similar subcellular distribution of the Kir2.1 protein with high intensity labelling from the membrane region, demonstrating normal membrane trafficking of the Val302del Kir2.1 variant. Cells transfected with the WT allele displayed a robust current with strong inward rectification, while no current above background was detected in cells expressing the Val302del Kir2.1 subunit. Co-transfection of CHO cells with the WT and the Val302del Kir2.1 revealed a dose-dependent inhibitory effect of the Val302del Kir2.1 mutant subunit on WT Kir2.1 currents. These observations indicate that the WT and the Val302del mutant subunits co-assemble in the cell membrane and that the mutation affects potassium conductivity and (or) gating of the WT/Val302del heteromeric Kir2.1 channels.

scholarly journals Influence of Ferroportin Disease Mutations on Manganese Accumulation and Toxicity (P24-060-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Eun-kyung Choi ◽  
Young-Ah Seo
Keyword(s):  
Genetic Disorder ◽  
Functional Results ◽  
Site Directed Mutagenesis ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Excess Iron ◽  
Funding Sources ◽  
Disease Mutations ◽  
The Impact

Abstract Objectives Hemochromatosis is a frequent genetic disorder characterized by the accumulation of excess iron across tissues. Mutations in the FPN1 gene, encoding a cell-surface iron exporter ferroportin (Fpn), are responsible for hemochromatosis type 4, also known as ferroportin disease. Recently, Fpn has been implicated in the regulation of manganese (Mn), another essential nutrient required for numerous cellular enzymes. However, the roles of Fpn in Mn regulation remain ill defined, and the impact of disease mutations on cellular Mn levels is unknown. Thus, this study aimed to define the role of Fpn in Mn regulation and determine the functional consequences of ferroportin disease mutations in cellular Mn levels. Methods Thus far, over 50 mutations in Fpn have been identified in hemochromatosis type 4/ferroportin disease. To test whether these mutations alter cellular Mn metabolism, we constructed an expression vector encoding human Fpn with a C-terminal HA epitope tag and introduced nine clinically relevant mutations by site-directed mutagenesis. Based on previously reported in vitro functional results, we selected five ferroportin disease mutations from each of the two groups: five loss-of-function (LOF) mutations (G80S, R88G, D157G, D157Y, and V162Δ) and four gain-of-function (GOF) mutations (N144H, N144T, C326S, and and S338R). Results Here, we provide evidence that Fpn can export Mn from cells into extracellular space. Fpn appears to play protective roles in Mn-induced cellular toxicity and oxidative stress. Finally, disease mutations interfere with Fpn's role in controlling Mn levels as well as the stability of Fpn. Conclusions These results define the function of Fpn as an exporter of both iron and Mn and highlight the potential involvement of Mn dysregulation in ferroportin disease. Funding Sources National Institutes of Health (NIH) to Y.A.S. (K99/R00 ES024340).

Association analyses of depression and genes in the hypothalamus–pituitary–adrenal axis

2016 ◽  
Vol 29 (1) ◽  
pp. 59-64 ◽  
Author(s):  
Henrietta Nørmølle Buttenschøn ◽  
Jesper Krogh ◽  
Marit Nyholm Nielsen ◽  
Linda Kaerlev ◽  
Merete Nordentoft ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Genetic Variants ◽  
Stressful Life Events ◽  
Potential Candidate ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Association Analyses ◽  
Potential Candidate Gene ◽  
Potential Association

ObjectiveDysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been reported in depression. The aim was to investigate the potential association between depression and seven genes regulating or interfering with the HPA axis, including the gene encoding angiotensin converting enzyme (ACE).MethodsIn total, 78 single nucleotide polymorphisms (SNPs) and one insertion/deletion polymorphism were genotyped. The study included 408 individuals with depression and 289 controls. In a subset of cases, the interaction between genetic variants and stressful life events (SLEs) was investigated.ResultsAfter quality control, 68 genetic variants were left for analyses. Four of nine variants within ACE were nominally associated with depression and a gene-wise association was likewise observed. However, none of the SNPs located within AVP, CRH, CRHR1, CRHR2, FKBP5 or NC3C1 were associated with depression. One nominally significant interaction, most likely due to chance, was identified.ConclusionThe results indicate that ACE could be a potential candidate gene for depression.

scholarly journals Congenital B cell lymphocytosis explained by novel germline CARD11 mutations

2012 ◽  
Vol 209 (12) ◽  
pp. 2247-2261 ◽  
Author(s):  
Andrew L. Snow ◽  
Wenming Xiao ◽  
Jeffrey R. Stinson ◽  
Wei Lu ◽  
Benjamin Chaigne-Delalande ◽  
...  
Keyword(s):  
B Cell ◽  
Genetic Disorder ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Scaffolding Protein ◽  
Gene Encoding ◽  
B Cell Malignancy ◽  
Whole Transcriptome Sequencing ◽  
Similar Patient ◽  
Cell Malignancy

Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)–induced NF-κB activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-κB activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.

scholarly journals Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency

2016 ◽  
Vol 101 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Justine Bouilly ◽  
Isabelle Beau ◽  
Sara Barraud ◽  
Valérie Bernard ◽  
Kemal Azibi ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Gene Mutations ◽  
Primary Ovarian Insufficiency ◽  
Potential Candidate ◽  
Missense Mutations ◽  
Ovarian Insufficiency ◽  
Monogenic Disorder ◽  
Gene Encoding ◽  
Multiple Loci

Context: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. Objective: The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. Patients and Methods: One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. Results: At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. Conclusions: Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.

Caries and Innate Immunity: DEFB1 Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy

2016 ◽  
Vol 50 (6) ◽  
pp. 589-594 ◽  
Author(s):  
Chiara O. Navarra ◽  
Antonietta Robino ◽  
Nicola Pirastu ◽  
Lorenzo Bevilacqua ◽  
Paolo Gasparini ◽  
...  
Keyword(s):  
Snp Array ◽  
Potential Candidate ◽  
Nucleotide Polymorphisms ◽  
Isolated Populations ◽  
Gene Encoding ◽  
North Eastern ◽  
Dmft Index ◽  
Oral Pathogens ◽  
Genetic Isolates ◽  
Number Of Individuals

Background: The DEFB1 gene, encoding for the constitutively expressed human β-defensin 1 (hBD1) antimicrobial peptide is a potential candidate when studying genetic susceptibility to caries. DEFB1 genetic variations have been reported as contributing to hBD1 production impairment, leading to a greater susceptibility to be infected by oral pathogens, also leading to periodontitis. Methods: We analysed 5 DEFB1 polymorphisms, namely 3 functional single-nucleotide polymorphisms (SNPs) at the 5′-untranslated region (UTR), -52G>A (rs1799946), -44C>G (rs1800972), and -20G>A (rs11362), 2 SNPs at the 3′-UTR, c*5G>A (rs1047031) and c*87A>G (rs1800971) SNP located in potential miRNA binding sites, looking for possible correlations with the risk to develop caries in 654 adult subjects from isolated populations of north-eastern Italy. Dental caries prevalence was evaluated with the DMFT (decayed, missing, filled teeth) index, calculated after an accurate oral examination. DEFB1 SNP genotyping was performed with an Illumina 370k high-density SNP array. Results: Two DEFB1 SNPs were significantly associated with the DMFT index: the strongest association emerged from rs11362 SNP (p = 0.008). In particular G/G homozygous individuals showed a higher DMFT index compared to both G/A heterozygous and A/A homozygous individuals; rs1799946 SNP was also significantly associated with DMFT (p = 0.030), and individuals homozygous for the T allele had a higher DMFT value compared to heterozygous C/T and homozygous C/C individuals. Conclusions: Our study replicated, on a larger number of individuals, previous findings showing the association between two 5′-UTR SNPs in the DEFB1 gene and DMFT, suggesting that these polymorphisms could be considered as potential markers for assessing the risk to develop caries.

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