scholarly journals p53 Activation in Genetic Disorders: Different Routes to the Same Destination

2021 ◽  
Vol 22 (17) ◽  
pp. 9307
Author(s):  
Yu-Young Tsai ◽  
Chun-Hao Su ◽  
Woan-Yuh Tarn
Keyword(s):  
Developmental Disorders ◽  
Genetic Disorders ◽  
Pleiotropic Effect ◽  
Telomere Maintenance ◽  
Tumor Suppressor P53 ◽  
Inherited Disorders ◽  
Developmental Defects ◽  
Cellular Processes ◽  
Damage Repair ◽  
P53 Activation

The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.

Case report: a child with cystic fibrosis and phenylketonuria

2020 ◽  
Vol 1 (2) ◽  
pp. 38-44
Author(s):  
Irina V. Vakhlova ◽  
Anastasia D. Kazachina ◽  
Olga A. Beglyanina
Keyword(s):  
Cystic Fibrosis ◽  
Case Report ◽  
Clinical Practice ◽  
Neonatal Screening ◽  
Genetic Disorders ◽  
Epileptiform Activity ◽  
Autism Spectrum ◽  
Speech Development ◽  
Inherited Disorders ◽  
Congenital Diseases

Background. In the international clinical practice there have been occasional reports of phenylketonuria (PKU) and cystic fibrosis (CF) found simultaneously in the same patient. Both PKU and CF are the inherited disorders characterized by autosomal recessive type of inheritance. Currently the combination of two or more inherited disorders in one patient is considered to be a clinical rarity.Case description. This is a clinical case of two genetic disorders, CF and PKU, combined in a 5-year old patient who had been followed up since birth. Owing to implementation of neonatal screening for inherited and congenital diseases into clinical practice, during the first month of life the infant was diagnosed with CF (diagnostically significant elevation of immunoreactive trypsin [IRT] at the initial [163.2 ng/mL] and repeat testing on day 21 of life [138.7 ng/mL]) and PKU (phenylalanine [PA] level 15.9 mg/dL). Both disorders have been confirmed by genetic tests, i.e., homozygous DelF508 mutation was found in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and P281L mutation in the phenylalanine hydroxylase (PAH) gene was also present in homozygous state. Child’s parents strictly adhered to dietary and treatment recommendations. By the age of 5 years the child developed symptoms of neurological disorder and disorder of the respiratory system, cognitive impairment and delay in speech development, subclinical epileptiform activity with high risk of epilepsy, and chronic inflammation of the respiratory tract.Conclusion. This case report demonstrates the important role of neonatal screening in early diagnosis and timely start of therapy, and underscores the importance of continuous medication in such genetic disorders as CF and PKU. On the whole, such approach brings about a relative preservation of functioning of the most affected organs and systems. By the age of 5 years the child does not form bronchiectases, shows no signs of chronic hypoxia, nutritional deficiency or pronounced neurologic deficit, and is at low risk for the development of autism spectrum disorder. At the same time, the larger scale and longer-term observations are required in order to make the unequivocal conclusions about the prognosis of these diseases under conditions of modern-day medical follow-up.

scholarly journals Molecular regulation of Snai2 in development and disease

2019 ◽  
Vol 132 (23) ◽  
Author(s):  
Wenhui Zhou ◽  
Kayla M. Gross ◽  
Charlotte Kuperwasser
Keyword(s):  
Transcription Factor ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Zinc Finger Protein ◽  
Main Role ◽  
Biological Processes ◽  
Developmental Defects ◽  
Mesenchymal Transition ◽  
Damage Repair

ABSTRACT The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease.

scholarly journals Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes

2019 ◽  
Vol 105 (4) ◽  
pp. 384-389 ◽  
Author(s):  
Adam Jackson ◽  
Heather Ward ◽  
Rebecca Louise Bromley ◽  
Charulata Deshpande ◽  
Pradeep Vasudevan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Copy Number ◽  
Developmental Disorders ◽  
Drug Exposure ◽  
Genetic Disorders ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
In Utero ◽  
Developmental Problems ◽  
Number Of Children

IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).ConclusionsThis study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

scholarly journals Immunogenetics of the Ocular Anterior Segment: Lessons from Inherited Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Jasmine Y. Serpen ◽  
Stephen T. Armenti ◽  
Lev Prasov
Keyword(s):  
Immune System ◽  
Lupus Erythematosus ◽  
Genetic Disorders ◽  
Anterior Segment ◽  
Adaptive Immune System ◽  
Mendelian Inheritance ◽  
Ocular Involvement ◽  
Inherited Disorders ◽  
Molecular Features ◽  
Organ Systems

Autoimmune and autoinflammatory diseases cause morbidity in multiple organ systems including the ocular anterior segment. Genetic disorders of the innate and adaptive immune system present an avenue to study more common inflammatory disorders and host-pathogen interactions. Many of these Mendelian disorders have ophthalmic manifestations. In this review, we highlight the ophthalmic and molecular features of disorders of the innate immune system. A comprehensive literature review was performed using PubMed and the Online Mendelian Inheritance in Man databases spanning 1973–2020 with a focus on three specific categories of genetic disorders: RIG-I-like receptors and downstream signaling, inflammasomes, and RNA processing disorders. Tissue expression, clinical associations, and animal and functional studies were reviewed for each of these genes. These genes have broad roles in cellular physiology and may be implicated in more common conditions with interferon upregulation including systemic lupus erythematosus and type 1 diabetes. This review contributes to our understanding of rare inherited conditions with ocular involvement and has implications for further characterizing the effect of perturbations in integral molecular pathways.

Congenital disorders

2018 ◽  
pp. 160-163
Author(s):  
Sowmiya Moorthie
Keyword(s):  
Developmental Disorders ◽  
Genetic Disorders ◽  
Holistic Approach ◽  
Congenital Disorders ◽  
Mortality And Morbidity ◽  
Specialist Services ◽  
Wide Range ◽  
Effective Delivery ◽  
The Life Course ◽  
Preventative Services

Congenital disorders encompass a wide range of conditions (e.g. genetic disorders, foetal disease, and developmental disorders) that occur before birth and are an important contributor to mortality and morbidity worldwide. Congenital disorders can be identified at different life stages and effective health services take a holistic approach to their care and prevention. This involves both population health and specialist services across the life course. Systematic collection of data on the types, prevalence, severity, and outcomes of congenital disorders, along with analysis and interpretation of data helps to inform appropriate planning of care and preventative services and activities. Important concepts in relation to congenital disorders, prevention activities, and key challenges to their effective delivery are described in this chapter.

scholarly journals Hedgehog Signaling and Embryonic Craniofacial Disorders

2019 ◽  
Vol 7 (2) ◽  
pp. 9 ◽  
Author(s):  
Abramyan
Keyword(s):  
Hedgehog Signaling ◽  
Developmental Disorders ◽  
Critical Role ◽  
Hedgehog Pathway ◽  
Developmental Defects ◽  
Downstream Target ◽  
Secondary Palate ◽  
The Face ◽  
Range Of Functions ◽  
Key Aspects

Since its initial discovery in a Drosophila mutagenesis screen, the Hedgehog pathway has been revealed to be instrumental in the proper development of the vertebrate face. Vertebrates possess three hedgehog paralogs: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). Of the three, Shh has the broadest range of functions both in the face and elsewhere in the embryo, while Ihh and Dhh play more limited roles. The Hedgehog pathway is instrumental from the period of prechordal plate formation early in the embryo, until the fusion of the lip and secondary palate, which complete the major patterning events of the face. Disruption of Hedgehog signaling results in an array of developmental disorders in the face, ranging from minor alterations in the distance between the eyes to more serious conditions such as severe clefting of the lip and palate. Despite its critical role, Hedgehog signaling seems to be disrupted through a number of mechanisms that may either be direct, as in mutation of a downstream target of the Hedgehog ligand, or indirect, such as mutation in a ciliary protein that is otherwise seemingly unrelated to the Hedgehog pathway. A number of teratogens such as alcohol, statins and steroidal alkaloids also disrupt key aspects of Hedgehog signal transduction, leading to developmental defects that are similar, if not identical, to those of Hedgehog pathway mutations. The aim of this review is to highlight the variety of roles that Hedgehog signaling plays in developmental disorders of the vertebrate face.

scholarly journals Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

2019 ◽  
Vol 116 (36) ◽  
pp. 17990-18000 ◽  
Author(s):  
Shatha AbuHammad ◽  
Carleen Cullinane ◽  
Claire Martin ◽  
Zoe Bacolas ◽  
Teresa Ward ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Negative Regulator ◽  
Cyclin Dependent Kinase ◽  
Tumor Suppressor P53 ◽  
Estrogen Receptor Positive ◽  
P53 Activation ◽  
Key Driver ◽  
Tumor Types ◽  
Emergence Of Resistance ◽  
Positive Breast Cancer

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

scholarly journals Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1535
Author(s):  
Renata Tisi ◽  
Vadim Gaponenko ◽  
Marco Vanoni ◽  
Elena Sacco
Keyword(s):  
Natural Products ◽  
Mammalian Cells ◽  
Developmental Disorders ◽  
Health Gain ◽  
Point Mutations ◽  
Ras Signaling ◽  
Cellular Processes ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Critical Issues

RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources.

scholarly journals Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

2020 ◽  
Vol 21 (24) ◽  
pp. 9451
Author(s):  
Marijn N. Maas ◽  
Jordi C. J. Hintzen ◽  
Miriam R. B. Porzberg ◽  
Jasmin Mecinović
Keyword(s):  
Protein Function ◽  
Genetic Disorders ◽  
Enzymatic Reactions ◽  
Lysine Methylation ◽  
Nucleosome Assembly ◽  
Cellular Processes ◽  
Subsequent Effect ◽  
Control Protein ◽  
Epigenetic Processes

Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.

Inherited Metabolic Diseases (IMDs) and Pregnancy

2018 ◽  
Author(s):  
Ahmed I. Ahmed ◽  
Sarah Aldhaheri ◽  
Allison Bannick
Keyword(s):  
Metabolic Diseases ◽  
Genetic Disorders ◽  
Acid Oxidation ◽  
Childbearing Age ◽  
Inherited Disorders ◽  
Inherited Metabolic Diseases ◽  
Neurological Outcomes ◽  
Maternal Metabolism ◽  
Pregnancy And Postpartum ◽  
Cycle Disorders

Inherited metabolic diseases (IMDs) are rare genetic disorders: clinically heterogeneous, and they can present at any age. With the expanded newborn screening panels, many of the IMDs have been successfully screened. Early diagnosis and treatment of these conditions have led to improved neurological outcomes and overall survival of these individuals, and now many of them are reaching childbearing age. Despite treatment, the potential presence of preexisting organ involvement may not only impact their fertility potentials but also may impose a higher risk of adverse maternal and fetal outcomes. Pregnancy leads to an extra strain on maternal metabolism; this may result in the manifestation of symptoms of a previously unknown disease or a progression of a known disease. This chapter will address the possible complications of some inherited disorders of metabolism that are associated with maternal or fetal neurological manifestations such as disorders of energy metabolism (eg, mitochondrial disorders, adult onset urea cycle disorders, ornithine transcarbamylase (OTC) deficiency, amino acidopathies, phenylketonuria (PKU), and impaired fatty acid oxidation disorders). We will provide special emphasis on the available potential treatments and plan of care during pregnancy and postpartum periods.

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