Normal Organ Development Research Articles

Characterisation and evolution of the PRC2 complex and its functional analysis under various stress conditions in rice

The polycomb repressive complex 2 (PRC2) is a chromatin-associated methyltransferase responsible for catalysing the trimethylation of H3K27, an inhibitory chromatin marker associated with gene silencing. This enzymatic activity is crucial for normal organismal development and the maintenance of gene expression patterns that preserve cellular identity, subsequently influencing plant growth and abiotic stress responses. Therefore, in this study, we investigated the evolutionary characteristics and functional roles of PRC2 in plants. We identified 209 PRC2 genes, including E(z), Su(z), Esc, and Nurf55 families, using 18 representative plant species and revealed that recent gene replication events have led to an expansion in the Nurf55 family, resulting in a greater number of members compared to the E(z), Su(z), and Esc families. Furthermore, protein structure and motif composition analyses highlighted the potential functional site regions within PRC2 members. In addition, we selected rice, a representative monocotyledonous plant, as the model species for food crops. Our findings revealed that SDG711, SDG718, and MSI1-5 genes were induced by abscisic acid (ABA) and/or methyl jasmonate (MeJA) hormones, suggesting that these genes play an important role in abiotic stress and disease resistance. Further experiments involving rice blast fungus treatments confirmed that the expression of SDG711 and MSI1-5 was induced by Magnaporthe oryzae strain GUY11. Multiple protein interaction assays revealed that the M. oryzae effector AvrPiz-t interacts with PRC2 core member SDG711 to increase H3K27me3 levels. Notably, inhibition of PRC2 or mutation of SDG711 enhanced rice resistance to M. oryzae. Collectively, these results provide new insights into PRC2 evolution in plants and its significant functions in rice.

Systemic in utero gene editing as a treatment for cystic fibrosis.

In utero gene editing has the potential to modify disease causing genes in multiple developing tissues before birth, possibly allowing for normal organ development, disease improvement, and conceivably, cure. In cystic fibrosis (CF), a disease that arises from mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, there are signs of multiorgan disease affecting the function of the respiratory, gastrointestinal, and reproductive systems already present at birth. Thus, treating CF patients early is crucial for preventing or delaying irreversible organ damage. Here we demonstrate proof-of-concept of multiorgan mutation correction in CF using peptide nucleic acids (PNAs) encapsulated in polymeric nanoparticles and delivered systemically in utero. In utero editing was associated with sustained postnatal CFTR activity, at a level similar to that of wild-type mice, in both respiratory and gastrointestinal tissue, without detection of off-target mutations in partially homologous loci. This work suggests that systemic in utero gene editing represents a viable strategy for treating monogenic diseases before birth that impact multiple tissue types.

Surviving the Storm: The Role of Poly- and Depolyploidization in Tissues and Tumors.

Polyploidization and depolyploidization are critical processes in the normal development and tissue homeostasis of diploid organisms. Recent investigations have revealed that polyaneuploid cancer cells (PACCs) exploit this ploidy variation as a survival strategy against anticancer treatment and for the repopulation of tumors. Unscheduled polyploidization and chromosomal instability in PACCs enhance malignancy and treatment resistance. However, their inability to undergo mitosis causes catastrophic cellular death in most PACCs. Adaptive ploid reversal mechanisms, such as multipolar mitosis, centrosome clustering, meiosis-like division, and amitosis, counteract this lethal outcome and drive cancer relapse. The purpose of this work is to focus on PACCs induced by cytotoxic therapy, highlighting the latest discoveries in ploidy dynamics in physiological and pathological contexts. Specifically, by emphasizing the role of "poly-depolyploidization" in tumor progression, the aim is to identify novel therapeutic targets or paradigms for combating diseases associated with aberrant ploidies.

GD2-targeting therapy: a comparative analysis of approaches and promising directions.

Disialoganglioside GD2 is a promising target for immunotherapy with expression primarily restricted to neuroectodermal and epithelial tumor cells. Although its role in the maintenance and repair of neural tissue is well-established, its functions during normal organism development remain understudied. Meanwhile, studies have shown that GD2 plays an important role in tumorigenesis. Its functions include proliferation, invasion, motility, and metastasis, and its high expression and ability to transform the tumor microenvironment may be associated with a malignant phenotype. Structurally, GD2 is a glycosphingolipid that is stably expressed on the surface of tumor cells, making it a suitable candidate for targeting by antibodies or chimeric antigen receptors. Based on mouse monoclonal antibodies, chimeric and humanized antibodies and their combinations with cytokines, toxins, drugs, radionuclides, nanoparticles as well as chimeric antigen receptor have been developed. Furthermore, vaccines and photoimmunotherapy are being used to treat GD2-positive tumors, and GD2 aptamers can be used for targeting. In the field of cell therapy, allogeneic immunocompetent cells are also being utilized to enhance GD2 therapy. Efforts are currently being made to optimize the chimeric antigen receptor by modifying its design or by transducing not only αβ T cells, but also γδ T cells, NK cells, NKT cells, and macrophages. In addition, immunotherapy can combine both diagnostic and therapeutic methods, allowing for early detection of disease and minimal residual disease. This review discusses each immunotherapy method and strategy, its advantages and disadvantages, and highlights future directions for GD2 therapy.

Hexosamine biosynthesis and related pathways, protein N-glycosylation and O-GlcNAcylation: their interconnection and role in plants.

N-Acetylglucosamine (GlcNAc), a fundamental amino sugar moiety, is essential for protein glycosylation, glycolipid, GPI-anchor protein, and cell wall components. Uridine diphosphate-GlcNAc (UDP-GlcNAc), an active form of GlcNAc, is synthesized through the hexosamine biosynthesis pathway (HBP). Although HBP is highly conserved across organisms, the enzymes involved perform subtly distinct functions among microbes, mammals, and plants. A complete block of HBP normally causes lethality in any life form, reflecting the pivotal role of HBP in the normal growth and development of organisms. Although HBP is mainly composed of four biochemical reactions, HBP is exquisitely regulated to maintain the homeostasis of UDP-GlcNAc content. As HBP utilizes substrates including fructose-6-P, glutamine, acetyl-CoA, and UTP, endogenous nutrient/energy metabolites may be integrated to better suit internal growth and development, and external environmental stimuli. Although the genes encoding HBP enzymes are well characterized in microbes and mammals, they were less understood in higher plants in the past. As the HBP-related genes/enzymes have largely been characterized in higher plants in recent years, in this review we update the latest advances in the functions of the HBP-related genes in higher plants. In addition, HBP's salvage pathway and GlcNAc-mediated two major co- or post-translational modifications, N-glycosylation and O-GlcNAcylation, are also included in this review. Further knowledge on the function of HBP and its product conjugates, and the mechanisms underlying their response to deleterious environments might provide an alternative strategy for agricultural biofortification in the future.

An entropy-based approach for assessing the directional persistence of cell migration

Cell migration, which is primarily characterized by directional persistence, is essential for the development of normal tissues and organs, as well as for numerous pathological processes. However, there is a lack of simple and efficient tools to analyze the systematic properties of persistence based on cellular trajectory data. Here, we present a novel approach, the entropy of angular distribution , which combines cellular turning dynamics and Shannon entropy to explore the statistical and time-varying properties of persistence that strongly correlate with cellular migration modes. Our results reveal the changes in the persistence of multiple cell lines that are tightly regulated by both intra- and extracellular cues, including Arpin protein, collagen gel/substrate, and physical constraints. Significantly, some previously unreported distinctive details of persistence have also been captured, helping to elucidate how directional persistence is distributed and evolves in different cell populations. The analysis suggests that the entropy of angular distribution-based approach provides a powerful metric for evaluating directional persistence and enables us to better understand the relationships between cellular behaviors and multiscale cues, which also provides some insights into the migration dynamics of cell populations, such as collective cell invasion.

COMPARATIVE MORPHOLOGY OF THE PRENATAL DEVELOPMENT OF THE URINARY SYSTEM OF HUMAN AND DOMESTIC PIG (SUS DOMESTICA)

Objective – to determine the peculiarities of the sources of the bookmark and thechronological sequence of topographical and anatomical transformations of the organsand structures of the urinary system of humans and domestic pigs.Materials and methods. The study was performed on 14 series of consecutive histologicalsections of preparations of human embryos and pre-fetuses aged from 4 to 11 weeks ofintrauterine development (UTD) and 8 series of histological sections of preparations ofembryos and pre-fetuses of domestic pigs. For a comparative analysis of the developmentof humans and domestic pigs in UTD, Carnegie stages of prenatal development (CS)were used to periodize embryogenesis. A complex of modern methods of morphologicalresearch (anthropometry, morphometry, microscopy, three- dimensional computerreconstruction, statistical analysis) was used.Results. Skeletotopically, the mesonephros in pig embryos was located between T1and S2 at stages from CS13 to CS16. During the CS19 stage, the cranial border of themesonephros was detected at the level of T2, with further stages continuing to migratefrom CS21 to T7 and from CS23 to L3. The caudal border of the porcine mesonephrosextended to S3 during stages CS19-CS23. When comparing the early stage of human and pig mesonephros development, it wasestablished that at the CS13 stage, the cranial border of the mesonephros was locatedat the T1/T2 level. During further development, the cranial boundary shifted to L4/L5 inhuman embryos, whereas in pig embryos these changes began at CS19, i. e. six stageslater. It was found that the caudal border of the mesonephros in human and pig embryoswas located at S1-S3 throughout development. Thus, human and pig mesonephros hadsimilar, constant caudal borders.During the differential growth of the mesonephros, the mesonephric duct graduallychanged its position from dorsolateral to ventrolateral relative to the mesonephrosin humans at CS16-CS18 stages, and to ventromedial position in pig embryos duringCS16-CS19 stages. These changes in the position of the mesonephric duct indicate thatthe growth process of the mesonephros occurs more intensively in the dorsal part.Conclusions. The use of systematized data on the intrauterine development of pigsallows to optimize the study of normal and pathological development of organs of thegenitourinary system of pigs, which is promising for modeling diseases in humans.

Tetralogy of Fallot: Hypoxia, the villain of the story?

Tetralogy of Fallot (ToF) is a cyanotic congenital heart disease, composed of four malformations: persistent communication between the right and the left ventricle, pulmonary stenosis, overriding aorta, and right ventricle hypertrophy. The etiology of this disease is not entirely known as yet, but it has been proposed that the pathology has genetic components. During embryonic development, the fetus is exposed to a physiological hypoxia to facilitate the formation of blood vessels and blood cells through de novo processes. After researching scientific databases on the implications of oxygen on the normal and abnormal development of organs, especially the heart, we were able to propose that oxygen deprivation may be the cause of the disease. During this period, the hypoxia-inducible factor is activated and triggers transcriptional responses that enable adaptation to the hypoxic environment through angiogenic activation. High levels of this protein can alter certain physiological pathways, such as those related to the vascular endothelial growth factor. Research has shown that prolonged oxygen deprivation during embryological development can lead to the occurrence of congenital heart diseases, such as ToF. Studies using animal models have demonstrated that the deficiency or disruption of a protein called "CITED2," which plays an important role in cardiac morphogenesis and its loss, results in the alteration of pluripotent, cardiac, and neural lineage differentiation, thereby disrupting the normal development of the heart and other tissues.

Fibroblast Growth Factor 21: A Fascinating Perspective on the Regulation of Muscle Metabolism.

Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external factors such as endogenous hormone changes and exogenous stimuli. Over the last few decades, comprehensive studies have revealed the key role of FGF21 in regulating many fundamental metabolic pathways, including the muscle stress response, insulin signaling transmission, and muscle development. By coordinating these metabolic pathways, FGF21 is thought to contribute to acclimating to a stressful environment and the subsequent recovery of cell and tissue homeostasis. With the emphasis on FGF21, we extensively reviewed the research findings on the production and regulation of FGF21 and its role in muscle metabolism. We also emphasize how the FGF21 metabolic networks mediate mitochondrial dysfunction, glycogen consumption, and myogenic development and investigate prospective directions for the functional exploitation of FGF21 and its downstream effectors, such as the mammalian target of rapamycin (mTOR).

Bioinformatic analysis of the ABC transporter protein family and their function in Penicillium digitatum

ATP-binding cassette transporter (ABC transporter) has prominent effects on the normal growth, development, substance transport and drug detoxification of organisms. However, the function of most of the ABC family members in filamentous fungi remains unknown. In the present research, 171 ABCs were identified from fruit postharvest pathogenic Penicillium spp. fungi including P. digitatum, P. expansum and P. italicum, of which 45 were from P. digitatum. Bioinformatics analysis showed that all 45 PdABCs had ABC_tran domain, belonging to seven subfamilies and containing 1–12 introns, distributed on six chromosomes of P. digitatum. The transcriptome data of spore germination, infection and sodium dehydroacetate (SD) inhibition showed that 43 PdABCs were detected as expressed in at least one stage, 6 PdABCs were all significantly differenially expressed during spore germination, infection or SD repression, five, eight and six PdABCs were significantly differentially expressed at the spore germination, infection and SD repression stages, respectively. RT-qPCR experiments further validated these six co-differentially expressed PdABCs. Cis-acting element (CAE) analysis showed that C2H2, C6 and Heat shock factors family-specific binding elements were highly present in their promoters, and the interaction regulatory network analysis indicated that there were interactions between PdABCs and PdABCs, major facilitator superfamily (MFS) transporter proteins, cytochrome P450 proteins, TFs (PdRING1、PdHeat1、PdbZIP1、PdzincC6). This study contributes to the screening of key ABCs and provides foundations for further investigation into the function of PdABCs and the creation of novel antifungal drugs to combat citrus green mold.

OR11-04 Activatable Glucocorticoid Receptor Agonists As Treatments For The Consequences Of Preterm Birth

Abstract Disclosure: R.S. Dhavan: None. K.L. Short: None. J. Ng: None. M.J. Wallace: None. P. Monaghan-Nichols: None. D. DeFranco: None. T.J. Cole: None. Glucocorticoid (GC) signaling is essential for normal fetal organ development. During late gestation a surge of endogenous GCs contributes to organ maturation, particularly important for the lung where thinning the mesenchymal tissue cause an increased alveolar-gas exchange surface area and decreased gas-exchange diffusion distance that is critical for lung function after birth. Currently potent synthetic GCs such as betamethasone (Bet) or dexamethasone (Dex) are administered antenatally to accelerate fetal lung maturation and reduce the risk of respiratory distress with preterm birth. There are however growing concerns that systemic exposure to powerful synthetic GCs such as Dex is associated with detrimental side effects, particularly in the developing fetal brain. We are currently assessing novel activatable and potentially partially selective agonists of the glucocorticoid receptor (GR) as new antenatal steroid treatments of preterm birth. One such GR agonist is a steroid prodrug called ciclesonide (Cic) that is activated in vivo to the GR agonist Des-Cic by a family of intracellular serine esterase enzymes, called carboxylesterases (Ces). We have previously demonstrated that postnatal administration of Cic and Dex drive similar stimulation of important preterm lung-specific biomarkers but in contrast to Dex, Cic produced no postnatal growth retardation, no reduction in brain weight, and no alteration in levels of neural myelination. In this current study we show by western blot analysis and immunofluorescence that the CES enzymes are expressed strongly in epithelial cells and the mesenchyme of peripheral organs such as the lung and kidney but are expressed at very low levels in the fetal and adult mouse brain, providing a basis for the preferential activation of Cic to Des-Cic only in peripheral organs. To examine the transcriptome changes induced by Cic vs Dex in the fetal mouse lung we have assessed cultured primary mouse fetal fibroblasts (the primary cell target for GCs during lung development) stimulated by 1μM Dex and Cic, for 6 hours. Changes in the fibroblast transcriptome was assessed by microarray analysis and relevant targets validated by real-time-qPCR. Analysis of the top 30 induced and repressed gene targets, including Fkbp5, Crispld2, Tgm2 and Zbtb16, demonstrated that Dex and Cic have almost identical activity profiles. Induction of transcriptional changes was completely lost in GR-null- derived fetal lung fibroblasts demonstrating specificity via the GR. The data suggests that Cic is able to regulate a respiratory genomic signature similar to Dex. Further studies will examine the effects of Cic vs Beta and Dex in mouse models of preterm birth, particularly in the context of unwanted side-effects in neural development. Presentation: Friday, June 16, 2023

Role of fibroblast growth factor 8 in different cancers

Fibroblast growth factor 8 (FGF8), a secretory protein of the FGF family, is highly expressed during early developmental stages. The early-stage expression of FGF8 and its isoforms is crucial for the normal development of organisms, while their expressions in adulthood are limited to the steroid hormone-targeting tissues. Interestingly, differential expression of FGF8 has been associated with the progression of various cancer types including breast, prostate, and ovarian cancers. Specifically, in gynecological cancers, the expression of FGF8 is regulated by steroid hormones. FGF8 isoforms, that is, FGF8a, FGF8b, FGF8e, and FGF8f act through different fibroblast growth factor receptors in different cancers through three main signaling pathways – MAP/RAS kinase, AKT/PI3, and PCLγ. This short review article discusses the structure and functions of FGF-8, along with its role in different cancers.

Role of Peptidylarginine Deiminase 4 in Central Nervous System Diseases.

The deimination or citrullination of arginine residues in the polypeptide chain by peptidylarginine deiminase 4 alters the charge state of the polypeptide chain and affects the function of proteins. It is one of the main ways of protein post-translational modifications to regulate its function. Peptidylarginine deiminase 4 is widely expressed in multiple tissues and organs of the body, especially the central nervous system, and regulates the normal development of organisms. The abnormal expression and activation of peptidylarginine deiminase 4 is an important pathological mechanism for the occurrence and development of central nervous system diseases such as multiple sclerosis, Alzheimer's disease, cerebral ischemia reperfusion injury, and glioblastoma.

LAX1, functioning with MADS-box genes, determines normal palea development in rice

Normal floral organ development in rice is necessary for grain formation. Many MADS-box family genes that belong to ABCDE model have been widely implicated in rice flower development. The LAX1 allele encodes a plant-specific basic helix-loop-helix (bHLH) transcription factor, which is the main regulator of axillary meristem formation in rice. However, the molecular mechanisms of LAX1 allele together with MADS-box family genes underlying palea development have not been reported. We found a short palea mutant plant in a population of indica rice variety 9311 treated with cobalt 60. We report the map-based cloning and characterization of lax1-7, identified as a new mutant allele of the LAX1 locus, and the role of its wild-type allele LAX1 in rice palea development. Through complementary experiments, combined with genetic and molecular biological analyses, the function of the LAX1 allele was determined. We showed that LAX1 allele is expressed specifically in young spikelets and encodes a nucleus-localized protein. In vitro and in vivo experiments revealed that the LAX1 protein physically interacts with OsMADS1, OsMADS6 and OsMADS7. The LAX1 allele is pleiotropic for the maintenance of rice palea identity via cooperation with MADS-box genes and other traits, including axillary meristem initiation, days to heading, plant height, panicle length and spikelet fertility.

Delayed abscission in animal cells - from development to defects.

Cell division involves separating the genetic material and cytoplasm of a mother cell into two daughter cells. The last step of cell division, abscission, consists of cutting the cytoplasmic bridge, a microtubule-rich membranous tube connecting the two cells, which contains the midbody, a dense proteinaceous structure. Canonically, abscission occurs 1-3 h after anaphase. However, in certain cases, abscission can be severely delayed or incomplete. Abscission delays can be caused by mitotic defects that activate the abscission 'NoCut' checkpoint in tumor cells, as well as when cells exert abnormally strong pulling forces on the bridge. Delayed abscission can also occur during normal organism development. Here, we compare the mechanisms triggering delayed and incomplete abscission in healthy and disease scenarios. We propose that NoCut is not a bona fide cell cycle checkpoint, but a general mechanism that can control the dynamics of abscission in multiple contexts.

Long Non-Coding RNAs as Emerging Targets in Lung Cancer.

Long non-coding RNAs (LncRNAs) are mRNA-like molecules that do not encode for proteins and that are longer than 200 nucleotides. LncRNAs play important biological roles in normal cell physiology and organism development. Therefore, deregulation of their activities is involved in disease processes such as cancer. Lung cancer is the leading cause of cancer-related deaths due to late stage at diagnosis, distant metastasis, and high rates of therapeutic failure. LncRNAs are emerging as important molecules in lung cancer for their oncogenic or tumor-suppressive functions. LncRNAs are highly stable in circulation, presenting an opportunity for use as non-invasive and early-stage cancer diagnostic tools. Here, we summarize the latest works providing in vivo evidence available for lncRNAs role in cancer development, therapy-induced resistance, and their potential as biomarkers for diagnosis and prognosis, with a focus on lung cancer. Additionally, we discuss current therapeutic approaches to target lncRNAs. The evidence discussed here strongly suggests that investigation of lncRNAs in lung cancer in addition to protein-coding genes will provide a holistic view of molecular mechanisms of cancer initiation, development, and progression, and could open up a new avenue for cancer treatment.

Specific fetal malformations following intrauterine exposure to antiseizure medication

ObjectiveTo investigate in the Australian Pregnancy Register of Antiepileptic Drugs patterns of fetal malformation associated with intrauterine exposure to particular currently available antiseizure medications taken by women with epilepsy. ResultsThere was statistically significant evidence (P < 0.05) of an increased hazard of fetal malformation associated with exposure to valproate, carbamazepine, topiramate, zonisamide, and with conception after assisted fertilization, but a reduced hazard in the offspring of women who continued to smoke during pregnancy. Valproate exposure was associated with malformations in a wide range of organs and organ systems, carbamazepine and topiramate with hydronephrosis, topiramate also with hypospadias, zonisamide with spina bifida and assisted fertilization with heart and great vessel maldevelopment. ConclusionsPrenatal valproate exposure appears to interfere with the development of many if not all, fetal tissues. It seems likely that prenatal exposure to carbamazepine and topiramate, and possibly exposure to zonisamide, but also some process related to in vitro fertilization, may more selectively affect the normal development of particular fetal tissues or organs.

Dye@MOF composites (RhB@1): Highly sensitive dual emission sensor for the detection of pesticides, Fe3+ and ascorbate acid

With the rapid development of economy, industrial and agricultural pollutants have caused great damage to the ecological environment and the normal development of organisms, posing a serious threat to global public health. Therefore, rapid and sensitive detection of pollutants is very important for environmental safety and people's health. A stable multi-response fluorescence sensor (RhB@1) with dual emission characteristics was constructed by embedding RhB guest molecules in Zn-MOF using a simple one-pot method. XRD, IR, XPS, Raman and other characterization methods were used to demonstrate the formation of composite materials. The sensor has two fluorescence emission peaks at 415 nm and 575 nm under the excitation of 316 nm. It has high sensitivity and low detection limit (7.94 and 7.82 nmol/L, respectively) in the detection of fluazinam (FLU) and Fe3+. The mechanism of fluorescence quenching may be due to the synergistic effect of IFE and PET. Outstandingly, when ascorbate acid (AA) was added to the quenching system of Fe3+ and RhB@1, its fluorescence gradually recovered, forming the unique “on-off-on” sensor. Therefore, RhB@1 has a fast fluorescence response and good stability, making it potentially useful in practical application and biosensors. More significantly, using Fe3+ and AA as chemical input signals, a binary intelligent logic gate device has been developed based on the “on-off-on” response mode of RhB@1, which extends the application of logic gate switching devices in the chemical field. In addition, a visual portable test paper with good selectivity and high sensitivity was developed, which can be used for rapid detection of FLU, showing its broad application prospect.

Advances in research of biological functions of Isthmin-1.

Isthmin-1 (ISM1) was initially thought to be a brain secretory factor, but with the development of technical means of research and the refinement of animal models, numerous studies have shown that this molecule is expressed in multiple tissues, suggesting that it may have multiple biological functions. As a factor that regulates growth and development, ISM1 is expressed in different animals with spatial and temporal variability and can coordinate the normal development of multiple organs. Recent studies have found that under the dependence of a non-insulin pathway, ISM1 can lower blood glucose, inhibit insulin-regulated lipid synthesis, promote protein synthesis, and affect the body's glucolipid and protein metabolism. In addition, ISM1 plays an important role in cancer development by promoting apoptosis and anti-angiogenesis, and by regulating multiple inflammatory pathways to influence the body's immune response. The purpose of this paper is to summarize relevant research results from recent years and to describe the key features of the biological functions of ISM1. We aimed to provide a theoretical basis for the study of ISM1 related diseases, and potential therapeutic strategies. The main biological functions of ISM1. Current studies on the biological functions of ISM1 focus on growth and development, metabolism, and anticancer treatment. During embryonic development, ISM1 is dynamically expressed in the zebrafish, African clawed frog, chick, mouse, and human, is associated with craniofacial malformations, abnormal heart localization, and hematopoietic dysfunction. ISM1 plays an important role in regulating glucose metabolism, lipid metabolism, and protein metabolism in the body. ISM1 affects cancer development by regulating cellular autophagy, angiogenesis, and the immune microenvironment.

The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Haploinsufficiency in SON may affect multiple genes, including those involved in the development and metabolism of multiple organs. Considering the broad spectrum of SON functions, it is to be expected that pathogenic variants in this gene can cause a wide spectrum of clinical symptoms. We present an additional ZTTK syndrome case due to a de novo heterozygous variant in the SON gene (c.5751_5754delAGTT). The clinical manifestations of our patient were similar to those present in previously reported cases; however, the diagnosis of ZTTK syndrome was delayed for a long time and was carried out during the diagnostic work-up of significant chronic liver disease (CLD). CLD has not yet been reported in any series; therefore, our report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement. Correspondingly, we recommend screening patients with SON variants specifically for liver involvement from the first years of life. Once the CLD has been diagnosed, an appropriate follow-up is mandatory, especially considering the role of SON as an emerging player in cancer development. Further studies are needed to investigate the role of SON haploinsufficiency as a downregulator of essential genes, thus potentially impairing the normal development and/or functions of multiple organs.