Mutations In Gene Research Articles

Templating of Monomeric Alpha-Synuclein Induces Inflammation and SNpc Dopamine Neuron Death in a Genetic Mouse Model of Synucleinopathy.

While the etiology of most cases of Parkinson's disease (PD) are idiopathic, it has been estimated that 5-10% of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (α-syn). α-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, α-syn misfolds into multimeric b-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HC, HPLC, and cytokine analysis, we examined the sequelae of intraparenchymal brain seeding of pre-formed fibrils (PFFs) and monomeric α-syn in C57BL/6J (WT) and A53T SNCA mutant mice. We found that injection of PFFs, but not monomeric α-syn, into the striatum of C57BL/6J mice induced spread of aggregated α-syn, loss of SNpc DA neurons and increased neuroinflammation. However, in A53T SNCA mice, we found that both PFFs and monomeric α-syn induced this pathology. This suggests that the conformation changes in α-syn seen in the A53T strain can recruit wild-type α-syn to a pathological misfolded conformation which may provide a mechanism for the induction of PD in humans with SNCA duplication/triplication.

Generation of Ext1 Gene-Edited Mice Model Via Dual sgRNAs/Cas9 System and Phenotypic Analyses.

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disease. Genetic linkage analyses have identified that mutations in the exostosin glycosyltransferase (EXT)1 and EXT2 genes are linked to HME pathogenesis, with EXT1 mutation being the most frequent. The aim of this study was to generate a mice model with Ext1 gene editing to simulate human EXT1 mutation and investigate the genetic pathogenicity of Ext1 through phenotypic analyses. We designed a pair of dual sgRNAs targeting exon 1 of the mice Ext1 gene for precise deletion of a 46bp DNA fragment, resulting in frameshift mutation of the Ext1 gene. The designed dual sgRNAs and Cas9 proteins were injected into mice zygotes cytoplasm. A total of 14 mice were obtained via embryo transfer, among which two genotypic chimera mice had a deletion of the 46bp DNA fragment in exon 1 of the Ext1 gene. By hybridization and breeding, we successfully generated heterozygous mice with edited Ext1 gene (Ext+/-). Off-target effect analysis did not reveal off-target mutations in Ext+/- mice caused by the two sgRNAs used. Compared to wild-type mice, Ext+/- mice exhibited lower body weights. X-ray imaging showed hyperplastic bone near caudal vertebrae only in male Ext+/- mice, with computed tomography values approximately at 200 HU for hyperplastic bone between ribs and spine regions. Furthermore, immunohistochemical analysis revealed fewer articular chondrocytes expressing EXT1 in edited mice compared to wild-type ones. Pathological section analysis demonstrated no structural or morphological abnormalities in heart, liver, lung, or kidney tissues from Ext+/- mice. In conclusion, we successfully generated an accurate DNA deletion model for studying Ext1 using dual sgRNAs/Cas9 systems. In conclusion, we successfully generated precise DNA deletions in the Ext1 mice model using the dual sgRNAs/Cas9 system. In conclusion, we observed significant phenotypic changes in Ext+/- mice, particularly bone hyperplasia in male individuals; however, no exostosis was detected in the gene-edited mice. The introduction of a frameshift mutation into the Ext1 gene through CRISPR/Cas9 technology resulted in novel phenotypic alterations, highlighting the genetic pathogenicity of Ext1. Therefore, our Ext+/- mice serve as a valuable model for further biomedical investigations related to the Ext1 gene.

BMAL1-Potential Player of Aberrant Stress Response in Q31L Mice Model of Affective Disorders: Pilot Results.

Dysregulation in the stress-response system as a result of genetical mutation can provoke the manifestation of affective disorders under stress conditions. Mutations in the human DISC1 gene is one of the main risk factors of affective disorders. It was known that DISC1 regulates a large number of proteins including BMAL1, which is involved in the regulation of glucocorticoid synthesis in the adrenal glands and the sensitivity of glucocorticoid receptor target genes. Male mice with a point mutation Q31L in the Disc1 gene were exposed to chronic unpredictable stress (CUS), after which the behavioral and physiological stress response assessed. To assess whether there were any changes in BMAL1 in key brain regions involved in the stress response, immunohistochemistry was applied. It was shown that the Q31L mice had an aberrant behavioral response, especially to the 2 weeks of CUS, which was expressed in unchanged motor activity, increased time of social interaction, and alterations in anxiety and fear-related behavior. Q31L males did not show an increase in blood corticosterone levels after CUS and a decrease in body weight. Immunohistochemical analysis in intact Q31L mice revealed a decrease in BMAL1 immunofluorescence in the CA1 hippocampal area and lateral habenula. Thus, the Q31L mutation of the Disc1 gene disrupts behavioral and physiological stress response and the BMAL1 dysregulation may underlie it, so this protein can act as a molecular target for the treatment of affective disorders.

Epidemiological and genetic characterization of the influenza A (H1N1) virus in Hangzhou City in 2023.

To explore and describe the epidemiological and genetic variation characteristics of the influenza A (H1N1) virus in Hangzhou City. Respiratory throat swab specimens collected from the fever clinic of the 903rd Hospital of the Chinese People's Liberation Army (PLA) between January and March 2023 were collected. The respiratory pathogen antigens were identified using the colloidal gold method, and those testing positive for influenza A virus antigens were confirmed and subtyped by RT-qPCR. Seventeen H1N1 isolates were selected to amplify hemagglutinin (HA) and neuraminidase (NA) gene sequences via RT-PCR, and sequencing was completed following the identification of the amplified products. The sequenced HA and NA sequences were spliced using DNASTAR software (version 5.0), and a phylogenetic tree was constructed using MEGA software (version 11.0) for genetic characterization. A total of 2,376 respiratory samples were tested, with 680 cases testing positive for influenza A. Of these, 129 positive cases of influenza A were randomly selected for typing, resulting in the isolation of 112 H1N1 subtypes and 17 H3N2 subtypes. The HA genes of 17 strains of influenza A (H1N1) were randomly selected for amino acid homology comparisons with two vaccine strains recommended by the WHO for 2023 (A/Wisconsin/67/2022 (H1N1) and A/Victoria/4897/2022 (H1N1)). The HA gene results showed identities of 98.24 to 98.65% and 98.41 to 98.82%, respectively, and the NA gene results were 98.79 to 99.15% and 98.94 to 99.29%, respectively. Fourteen amino acid sites were altered in the HA gene of the 17 strains, with some strains contributing to the Sa and Ca antigenic determinants, respectively. Seventeen strains had mutations in the NA gene at sites 13, 50, 200, 339, 382, and 469. The sequenced strains, vaccine strains, and some 2023 domestic representative strains independently formed a branch 6B.1A.5a.2a. The continuous evolutionary mutations of the H1N1 virus genes in Hangzhou City suggest the possibility of the virus escaping from the immune response. This study provides an experimental basis for evaluating the protective effect of the vaccine and formulating preventive measures against influenza in Hangzhou City.

Polyneuropathy in Cerebrotendinous Xanthomatosis: Diagnostic Challenges and Potential for Therapeutic Intervention.

Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disorder caused by mutations in the CYP27A1 gene, leading to cholestanol accumulation in various tissues, including peripheral nerves. Polyneuropathy is an underrecognized feature with considerable variability in clinical presentation and neurophysiological findings in CTX. This review assesses the prevalence, clinical manifestations, and diagnostic methodologies of polyneuropathy in CTX, exploring its underlying mechanisms and potential treatment outcomes. A literature review was conducted using PubMed, Embase, and the Virtual Health Library databases with search terms related to CTX and polyneuropathy. A total of 892 articles were initially identified, with 59 selected for in-depth analysis. The review focused on studies examining peripheral nerve involvement in CTX, including nerve conduction studies, electromyography, and nerve ultrasound. Polyneuropathy in CTX was observed in 50% to 77.7% of patients across multiple case series. Neurophysiological findings varied, with reports of axonal, demyelinating, and mixed polyneuropathies. Clinical presentation included lower limb atrophy, pes cavus, and distal weakness, with sensory symptoms less frequently reported. Treatment with chenodeoxycholic acid (CDCA) showed potential in improving nerve conduction parameters, although the response was variable and dependent on the timing of intervention. Polyneuropathy in CTX presents significant diagnostic challenges due to its heterogeneous presentation and varying neurophysiological findings. Early recognition and intervention are crucial for improving patient outcomes. Peripheral nerve ultrasound is a promising diagnostic tool, complementing traditional neurophysiological assessments. Further research is needed to standardize protocols and explore the full therapeutic potential of CDCA in managing CTX-related polyneuropathy.

Exploring the Structural and Functional Consequences of Deleterious Missense Nonsynonymous SNPs in the EPOR Gene: A Computational Approach.

Mutations in the EPOR gene can disrupt its normal signaling pathways, leading to hematological disorders such as polycythemia vera and other myeloproliferative diseases. In this study, a range of bioinformatics tools, including SIFT, PolyPhen-2, SNAP2, SNPs & Go, PhD-SNP, I-Mutant2.0, MuPro, MutPred, ConSurf, HOPE, and Interpro were used to assess the deleterious effects of missense nonsynonymous single nucleotide polymorphisms (nsSNPs) on protein structure and function. Furthermore, molecular dynamics simulations (MDS) were conducted to assess the structural deviations of the identified mutant variants in comparison to the wild type. The results identified two nsSNPs, R223P and G302S, as deleterious, significantly affecting protein structure and function. Both substitutions occur in functionally conserved regions and are predicted to be pathogenic, associated with altered molecular mechanisms. The MDSs indicated that while the wild-type EPOR maintained optimal stability, the G302S and R223P variants exhibited substantial deviations, adversely affecting overall protein stability and compactness. The computational analysis of missense nsSNPs in the EPOR gene identified two missense SNPs, R223P and G302S, as deleterious, occurring at highly conserved regions, and having substantial effects on erythropoietin receptor (EPO-R) protein structure and function, suggesting their potential pathogenic consequences.

Successful application of preimplantation genetic testing combined with thirdgeneration sequencing for blocking hereditary spastic paraplegia

We report a case of application of third-generation sequencing (TGS) combined with preimplantation genetic testing (PGT) for successful prevention of hereditary spastic paraplegia (HSP) caused by SPAST gene mutations and assess the value of PGT-M and TGS in managing hereditary spastic paraplegia. A family affected by HSP underwent whole exon sequencing (WES), and a c.1699G>T mutation in the SPAST gene was identified. The mutation site in the proband was confirmed through Sanger sequencing. A single nucleotide polymorphism (SNP) site flanking the SPAST gene mutation was selected as the genetic linkage marker, and a SNP haplotype carrying the mutated gene was constructed. Ovarian stimulation using an antagonist regimen was performed for oocyte retrieval, followed by intracytoplasmic sperm injection (ICSI) and embryo culture. Blastocyst trophectoderm cells were biopsied for preimplantation genetic testing for monogenic disorders (PGT-M) to allow the selection of disease-free embryos for transfer. In this cycle, a total of 20 oocytes were retrieved, among which 18 were successfully fertilized to result in 12 blastocysts eligible for biopsy. Genetic testing revealed that all the 12 blastocysts were successfully amplified and confirmed as euploidy. Among them, 8 blastocysts did not carry paternal mutations, and a high-quality euploid embryo was selected for frozen embryo transfer (FET). Subsequent amniotic fluid testing during pregnancy confirmed the absence of paternal mutations in the fetus, resulting in the birth of a healthy baby girl. For cases of genetic diseases with missing pedigree data, the application of third-generation sequencing and PGT-M technique can effectively block vertical transmission of SPAST gene mutation to the offspring, avoid pregnancy with an aneuploid embryo, and help families with autosomal dominant HSP obtain healthy offsprings.

A novel nonsense RPS26 mutation in a patient with Diamond–Blackfan anemia: a case report

BackgroundDiamond–Blackfan anemia is a rare congenital disorder characterized by erythroid hypoplasia and is associated with mutations in ribosomal protein genes. This case report describes a novel variant in the RPS26 gene, which, to our knowledge, has not been previously documented. Reporting this case adds to the understanding of Diamond–Blackfan anemia’s genetic diversity and phenotypic manifestations.Case presentationA 16-month-old Turkish girl presented with pallor and macrocytosis. There was no familial history of anemia. Hemoglobin electrophoresis showed hemoglobin F at 10.8%, hemoglobin A2 at 1.7%, and hemoglobin A at 87.5% (normal range 0–2%). Peripheral smear demonstrated macrocytosis and reticulocytopenia. Bone marrow examination revealed marked erythroid hypoplasia and dyserythropoiesis. Targeted next-generation sequencing, which included genes such as RPL11, RPL15, RPL26, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS28, RPS29, RPS7, and TSR2, identified a heterozygous c.221G>T (p.C74F) variant in the RPS26 gene. This variant is reported here for the first time.ConclusionsThe identification of the c.221G>T (p.C74F) variant in RPS26 provides new insights into the genetic underpinnings of Diamond–Blackfan anemia. This finding underscores the importance of genetic testing in diagnosing Diamond–Blackfan anemia and highlights the potential for new mutations to contribute to the clinical presentation of the disease. Further research into RPS26 mutations may enhance the understanding of Diamond–Blackfan anemia’s pathogenesis and lead to improved diagnostic and therapeutic strategies.

Olaparib promotes FABP4 expression and reduces antitumor effect in ovarian cancer cells with a BRCA1 mutation.

Olaparib (AZD2281) is used as a first-line maintenance treatment for patients with ovarian cancer (OC) with a breast cancer susceptibility gene (BRCA) mutation. Fatty acid binding protein 4 (FABP4) may serve an important role in cancer, but its role in olaparib-treated OC with a BRCA mutation requires further clarification. To explore the function of FABP4 and enhance the efficacy of AZD2281 in OC, cell counting kit-8, cell apoptosis, cell cycle, colony formation, cell transfection, western blotting, reverse transcription-quantitative polymerase chain reaction, chromatin immunoprecipitation, seahorse and reactive oxygen species assays were performed. In the present study, AZD2281 significantly promoted cell apoptosis, and inhibited cell cycle progression and colony formation in COV362 cells. In addition, AZD2281 significantly upregulated the levels of CCAAT enhancer binding protein α (CEBPα), peroxisome proliferator activated receptor γ (PPARγ) and FABP4. AZD2281 markedly promoted fold enrichment of CEBPα in the promoters of PPARγ and FABP4. Furthermore, FABP4 overexpression significantly decreased cell apoptosis and promoted cell cycle progression and colony formation. In contrast, FABP4 knockdown demonstrated the opposite effects. In addition, FABP4 significantly regulated levels of reactive oxygen species, adenosine triphosphate, aerobic glycolysis, basal respiration rate and fatty acid oxidation. The combination of AZD2281 with the FABP4 inhibitor BM S309403 further significantly increased cell apoptosis and decreased colony formation. In conclusion, the findings of the present study demonstrated that AZD2281 significantly enhanced FABP4 expression, leading to diminished antitumor efficacy in OC cells with a BRCA mutation by regulating CEBPα-PPARγ. Conversely, the combination of AZD2281 and FABP4 inhibitor BM S309403 demonstrated heightened antitumor effectiveness, presenting a promising therapeutic strategy for treating patients with OC with a BRCA mutation.

Genome-wide analyses of genomic diversity, population structure and selection signatures in Italian turkey populations

Italian local turkey populations are an important source of genetic diversity that should be preserved through an in vivo approach. Whole genome sequencing (WGS) and genotyping datasets were used to assess genetic variability within and across populations, to perform a genome-wide comparative analysis among populations and to identify selection signatures in Italian turkey populations. We used new data from 73 WGS samples (12X) representing five turkey populations, together with previous data from 107 birds genotyped with the Affymetrix 600K single nucleotide polymorphism (SNP) turkey array from 11 populations. The PCA and Admixture show a relatively strong isolation effect between the populations. Moreover, the values of genomic inbreeding based on ROH (FROH) showed marked differences among populations and ranged from 0.096 to 0.643. Selective sweeps were identified using the integrated haplotype score (iHS) within the local group, the commercial line, and the Narragansett breed, resulting in the identification of 20, 19, and 27 regions with a total of 73, 48, and 90 candidate genes, respectively. Some of these genes such as FAM107B, MSTN, PDZRN4, HSF2 and GJA1 are associated with heat stress, growth, and carcass traits. We conclude that our results improve our understanding of the genomic architecture of the Italian turkey populations. The findings of iHS suggest that selection can play a significant role in shaping selection signatures in local turkey populations and could provide a basis for identifying gene mutations that may be beneficial in adaptation to climate change. Our results will be useful in developing and implementing conservation and selection plans for Italian turkey populations.

The improvement of a refractory enterocutaneous fistula with colchicine in a patient with Crohn's disease who had an MEFV gene mutation.

Enterocutaneous fistulas (ECFs) occurring in the setting of Crohn's disease (CD) are difficult to cure with medical treatment alone and affects a patient's quality of life. A 39-year-old man was diagnosed with an ileocolitis-type CD in 2007. His inflammation was insufficiently controlled despite the administration of an anti-tumor necrosis factor-alpha antibody. Therefore, he underwent subtotal colectomy, terminal ileal resection, and ileostomy for multiple colon and anal stenoses in Dec 2015. The patient subsequently received ustekinumab; however, purulent discharge was observed from a postoperative scar around the umbilicus in July 2019. In July 2021, enteroscopy and magnetic resonance imaging (MRI) showed an ECF extending from the small intestine to the umbilicus. Upon referral to our hospital, laboratory data showed elevated C-reactive protein (CRP) and serum amyloid A (SAA). After receiving colchicine, his purulent discharge disappeared, and his CRP and SAA levels rapidly decreased. Enteroscopy and MRI performed 1year and 5months after the administration of colchicine revealed ECF closure. Genetic analysis revealed that the patient harbored an MEFV exon 1 (E84K) mutation.

Bmpr1aa modulates the severity of the skeletal phenotype in an fkbp10-deficient Bruck syndrome zebrafish model.

Rare monogenic disorders often exhibit significant phenotypic variability among individuals sharing identical genetic mutations. Bruck syndrome (BS), a prime example, is characterized by bone fragility and congenital contractures, although with a pronounced variability among family members. BS arises from recessive biallelic mutations in FKBP10 or PLOD2. FKBP65, the protein encoded by FKBP10, collaborates with the LH2 enzyme (PLOD2) in type I collagen telopeptide lysine hydroxylation, crucial for collagen cross-linking. To identify potential modifier genes and to investigate the mechanistic role of FKBP10 in BS pathogenesis, we established an fkbp10a knockout zebrafish model. Mass-spectrometry analysis in fkbp10a-/- mutants revealed a generally decreased type I collagen lysyl hydroxylation, paralleled by a wide skeletal variability similar to human patients. Ultrastructural examination of the skeleton in severely affected mutants showed enlarged type I collagen fibrils and disturbed elastin layers. Whole-exome sequencing of 7 mildly and 7 severely affected mutant zebrafish siblings, followed by SNP-based linkage analysis, indicated a linked region on chromosome 13, which segregates with phenotypic severity. Transcriptome analysis identified six differentially expressed genes (DEGs) between mildly and severely affected mutants. The convergence of genes within the linked region and DEGs highlighted bmpr1aa as a potential modifier gene, as its reduced expression correlates with increased skeletal severity. In summary, our study provides deeper insights into the role of FKBP10 in BS pathogenesis. Additionally, we identified a pivotal gene that influences phenotypic severity in a zebrafish model of BS. These findings hold promise for novel treatments in the field of bone diseases.

Living-donor liver transplantation for non-resectable colorectal liver metastases: protocol for a multicentric, single-arm study

IntroductionThe only treatment for non-resectable colorectal liver metastasis (CRLM) is medical therapy, and the overall survival (OS) rate at 3 and 5 years is approximately 30%–40% and less than 10%,...

Aberrant expression of MRAS and HEG1 as the biomarkers for osimertinib resistance in LUAD

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the most applied targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, osimertinib, is widely used throughout lung cancer treatment, with single or combination modes. One of the main barriers in osimertinib treatment is the acquired resistance and mechanisms are not fully understood. Gene expression other than genetic mutations might predict drug response and mediate resistance occurrence. We analyzed six datasets of osimertinib-resistant LUAD cells from the Gene Expression Omnibus (GEO) database and identified two hub genes, named MRAS and HEG1. We found that the expression mode of MRAS/HEG1 in LUAD was osimertinib-dependent and contributed to drug resistance. We also explored potential mechanisms of hub genes related osimertinib resistance and emphasized the M2 infiltration involved. Moreover, potential therapeutic agents conquering MRAS/HEG1-related resistance were also identified. In conclusion, MRAS and HEG1 might be responsible for osimertinib resistance and could be promising prognostic biomarkers for osimertinib response in LUAD, which might provide insights into therapeutic strategies.

Staphylococcus epidermidis ST2 strains associated with bloodstream infections contain a unique mobile genetic element encoding a plasmin inhibitor.

This study uncovers a new virulence mechanism in Staphylococcus epidermidis ST2 bloodstream isolates. We identify a mobile genetic element (MGE) characteristic of an integrated conjugated element (ICE). pICE-Sepi-ST2 carries the genetic information needed to produce a cell wall-anchored (CWA) protein called SesY. The results indicate that SesY binds to plasminogen (Plg) and plasmin (Pln) and inhibits Pln's degradation of fibrin clots. Genetic analysis showed that all ST2 bloodstream isolates can express the plasmin inhibitor SesY and carry a mutation in the SdrG gene, resulting in the expression of inactive SdrG. Thus, we describe a molecular pathway targeting the coagulation pathway that may be required for S. epidermidis ST2 to cause bloodstream infections.

A rare case of late-onset spondyloenchondrodysplasia with immune dysregulation presenting as adult-onset monogenic lupus.

Spondyloenchondrodysplasia is classified as an interferonopathy resulting from recessive mutations in the ACP5 gene and manifests with various clinical features, including distinctive skeletal dysplasia, neurological abnormalities, immune dysfunction resembling systemic lupus erythematosus (SLE) and Sjogren's syndrome. While SLE is typically considered multifactorial and more prevalent in adulthood, a subset of approximately 10%-25% of childhood cases arise from monogenic form. Among these, spondyloenchondrodysplasia accounts for only a rare fraction of monogenic lupus cases, with only 22 reported instances in the literature. This paper presents a new case of spondyloenchondrodysplasia-immune dysregulation (SPENCDI) in an adult patient born to nonconsanguineous parents. The patient was diagnosed with SPENCDI and exhibited immune neutropenia, anti-dsDNA positivity, platyspondyly, immune deficiency, and a homozygous variant (c.155A > C, p. Lys52Thr) in the ACP5 gene, previously classified as pathogenic. Notably, the patient achieved successful clinical management through the initiation of baricitinib treatment, a Janus kinase inhibitor. SPENCDI represents an uncommon cause of SLE in adulthood. Clinicians should be vigilant of underlying Mendelian inheritance when encountering patients with associated features. While treatments for both Mendelian and non-Mendelian SLE are similar, Janus kinase inhibitors like baricitinib show potential for managing interferon-signature monogenic SLE cases.

VEXAS Syndrome: A Comprehensive Review of Current Therapeutic Strategies and Emerging Treatments.

VEXAS syndrome is a recently identified autoinflammatory disorder resulting from somatic mutations in the UBA1 gene, leading to a complex spectrum of severe inflammatory and hematologic manifestations. The absence of established treatment guidelines and the variability in clinical presentation make its management particularly challenging. Current therapeutic approaches are often based on limited evidence, and their effectiveness remains inconsistent. This review seeks to consolidate the existing knowledge on therapeutic strategies for VEXAS syndrome, offering a critical evaluation of their efficacy and addressing the gaps in the current literature. As the clinical recognition of VEXAS grows, there is an urgent need to explore more targeted, effective treatments that can address both the inflammatory and hematologic aspects of the disease. By providing a comprehensive analysis of the current therapeutic landscape, this review aims to guide clinicians and researchers toward developing more effective, long-term management strategies for this life-threatening condition.

Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva (FOP): history, present, and future

Abstract Retinoids are metabolic derivatives of vitamin A and play crucial roles in the regulation of various tissues and organs during prenatal and postnatal development. Active retinoids, like all-trans-retinoic acid, are synthesized in the cytoplasm and subsequently interact with nuclear retinoic acid receptors (RARα, RARβ, and RARγ) to enhance transcription of specific genes. In the absence of retinoids, RARs can still bind to response elements of target genes but repress their transcription. Chondrogenic cell differentiation and cartilage maturation in the growth plate require the absence of retinoid signaling and transcriptional repression by unliganded RARs. This led to the hypothesis that synthetic retinoid agonists may be pharmacological agents to inhibit those cellular processes and counter the excessive formation of cartilage and bone in conditions like heterotopic ossification (HO). HO can be instigated by diverse culprits including trauma, invasive surgeries, inflammatory disorders, or genetic conditions. One such genetic disease is fibrodysplasia ossificans progressiva (FOP), a rare disorder driven by activating mutations in the ACVR1 gene. Patients with FOP have severe and progressive HO formation in soft tissues, leading to extensive permanent loss of mobility and increased mortality. Synthetic retinoid agonists selective for RARα or RARγ showed efficacy against injury-induced and genetic HO in mouse models. The RARγ agonists showed the highest effectiveness, with palovarotene being selected for clinical trials in patients with FOP. Post-hoc analyses of phase II and phase III clinical trials show that palovarotene has significant disease-modifying effects for FOP, but with significant risks such as premature growth plate closure in some younger subjects. This review provides an overview of retinoid and RAR roles in skeletal development and discusses the identification of palovarotene as a potential FOP therapy, the clinical data supporting its regulatory approval in some countries, and the potential applications of this drug for other relevant disorders besides FOP.

Analysis of a family with hypouricemia due to type Ⅰ xanthinuria

This article reports a patient presenting with"extremely low uric acid levels in blood and urine"clinically along with reviewing relevant literature to consider a diagnosis of xanthinuria. Peripheral blood samples of the patient and her family were further collected for xanthine dehydrogenase(XDH) gene sequencing, showing that the patient had compound heterozygous mutations in exon 19:c.1995_2006del12(p.His666_Gly669del) and exon 10:c.871G>T(p.Glu291*), however no mutations were found in the gene encoding MOCOS on chromosome 18, confirming the diagnosis of hereditary xanthinuria type Ⅰ.The patient's father, son and daughter carried heterozygous mutations in exon 19:c.1995_2006del12(p.His666_Gly669del), and the mother carried heterozygous mutations in exon 10:c.871G>T(p.Glu291*).Mutations in the XDH gene cause a lack of xanthine oxidoreductase function, which hinders the production of uric acid, leading to very low or undetectable levels in blood and urine. Patients present clinically with hematuria, renal colic, urolithiasis, and even acute renal failure. Through the diagnosis and treatment of this patient and literature review, the article aims to deepen the understanding of purine metabolism and uric acid production process, and improve the clinicians' diagnosis and treatment ability of hypouricemia.

Androgen receptor inhibitors in treating prostate cancer.

Androgens play an important role in prostate cancer development and progression. Androgen action is mediated through the androgen receptor (AR), a ligand-dependent DNA-binding transcription factor. AR is arguably the most important target for prostate cancer treatment. Current USA Food and Drug Administration (FDA)-approved AR inhibitors target the ligand-binding domain (LBD) and have exhibited efficacy in prostate cancer patients, particularly when used in combination with androgen deprivation therapy. Unfortunately, patients treated with the currently approved AR-targeting agents develop resistance and relapse with castration-resistant prostate cancer (CRPC). The major mechanism leading to CRPC involves reactivation of AR signaling mainly through AR gene amplification, mutation, and/or splice variants. To effectively inhibit the reactivated AR signaling, new approaches to target AR are being actively explored. These new approaches include novel small molecule inhibitors targeting various domains of AR and agents that can degrade AR. The present review provides a summary of the existing FDA-approved AR antagonists and the current development of some of the AR targeting agents.