Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network

Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach.

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Basics and disturbances of genomic imprinting

Medizinische Genetik ◽

10.1515/medgen-2020-2042 ◽

2020 ◽

Vol 32 (4) ◽

pp. 297-304

Author(s):

Dirk Prawitt ◽

Thomas Haaf

Keyword(s):

Genomic Imprinting ◽

Primordial Germ Cells ◽

Uniparental Disomy ◽

Point Mutations ◽

Paternal Allele ◽

Imprinted Genes ◽

Specific Expression ◽

Imprinting Disorders ◽

Increased Risk ◽

Genomic Imprints

Abstract Genomic imprinting ensures the parent-specific expression of either the maternal or the paternal allele, by different epigenetic processes (DNA methylation and histone modifications) that confer parent-specific marks (imprints) in the paternal and maternal germline, respectively. Most protein-coding imprinted genes are involved in embryonic growth, development, and behavior. They are usually organized in genomic domains that are regulated by differentially methylated regions (DMRs). Genomic imprints are erased in the primordial germ cells and then reset in a gene-specific manner according to the sex of the germline. The imprinted genes regulate and interact with other genes, consistent with the existence of an imprinted gene network. Defects of genomic imprinting result in syndromal imprinting disorders. To date a dozen congenital imprinting disorders are known. Usually, a given imprinting disorder can be caused by different types of defects, including point mutations, deletions/duplications, uniparental disomy, and epimutations. Causative trans-acting factors in imprinting disorders, including ZFP57 and the subcortical maternal complex (SCMC), have the potential to affect multiple DMRs across the genome, resulting in a multi-locus imprinting disturbance. There is evidence that mutations in components of the SCMC can confer an increased risk for imprinting disorders.

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Screening for imprinting disorders in 58 patients with clinically diagnosed idiopathic short stature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0198 ◽

2020 ◽

Vol 33 (10) ◽

pp. 1335-1339

Author(s):

Sayaka Kawashima ◽

Hiroko Yagi ◽

Yasuhiro Hirano ◽

Machiko Toki ◽

Kei Izumi ◽

...

Keyword(s):

Short Stature ◽

Clinical Diagnosis ◽

Standard Deviation Score ◽

Growth Failure ◽

Normal Growth ◽

Postnatal Growth ◽

Idiopathic Short Stature ◽

Imprinted Genes ◽

Imprinting Disorders ◽

Short Children

AbstractObjectivesImprinted genes have important roles for normal growth and development. Imprinting disorders (IDs) such as Silver-Russell syndrome and Temple syndrome are rare diseases that typically cause short children born small for gestational age (SGA). However, some patients with short stature (SS) caused by IDs were born non-SGA. To date, the contribution of IDs to idiopathic short stature (ISS) has been poorly investigated. The aim of this study was to clarify the contribution of IDs to ISS.MethodsWe conducted methylation analysis for 10 differentially methylated regions using pyrosequencing to detect known IDs in 58 patients (31 male and 27 female children, height standard deviation score −4.2 to −2.0) carrying a clinical diagnosis of ISS.ResultsWe identified no patient with IDs among these patients with ISS.ConclusionsThese results indicate that IDs are rare in patients having ISS, and that imprinted genes affect fetal growth more than postnatal growth. Because patients with IDs born non-SGA usually have clinical features characteristic of each ID, in addition to SS, the patients with ISS as a clinical diagnosis may not be associated with IDs.It is unlikely that cases clinically diagnosed with ISS are caused by IDs leading to growth failure.

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Nursing Interventions to Prevent Delirium in Critically Ill Patients in the Intensive Care Unit during the COVID19 Pandemic—Narrative Overview

Healthcare ◽

10.3390/healthcare8040578 ◽

2020 ◽

Vol 8 (4) ◽

pp. 578

Author(s):

Dorota Ozga ◽

Sabina Krupa ◽

Paweł Witt ◽

Wioletta Mędrzycka-Dąbrowska

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Critically Ill Patients ◽

Current Knowledge ◽

Personalised Medicine ◽

Nursing Interventions ◽

Evidence Based ◽

Current State ◽

Scientific Disciplines ◽

Reliable Methods

It has become a standard measure in recent years to utilise evidence-based practice, which is associated with a greater need to implement and use advanced, reliable methods of summarising the achievements of various scientific disciplines, including such highly specialised approaches as personalised medicine. The aim of this paper was to discuss the current state of knowledge related to improvements in “nursing” involving management of delirium in intensive care units during the SARS-CoV-2 pandemic. This narrative review summarises the current knowledge concerning the challenges associated with assessment of delirium in patients with COVID-19 by ICU nurses, and the role and tasks in the personalised approach to patients with COVID-19.

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Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽

10.3390/immuno1020006 ◽

2021 ◽

Vol 1 (2) ◽

pp. 78-90

Author(s):

Johannes Burtscher ◽

Grégoire P. Millet

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Cell Types ◽

Brain Cell ◽

Special Focus ◽

Molecular Alterations ◽

Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

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Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

Biological Chemistry ◽

10.1515/hsz-2021-0288 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Philipp Makowka ◽

Verena Stolp ◽

Karoline Stoschek ◽

Hubert Serve

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Current Knowledge ◽

Therapy Response ◽

Secondary Resistance ◽

Molecular Alterations ◽

Molecular Features ◽

Slow Progress ◽

Molecular Aberrations ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

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New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Vaccines ◽

10.3390/vaccines8020164 ◽

2020 ◽

Vol 8 (2) ◽

pp. 164 ◽

Cited By ~ 1

Author(s):

Stefania Scala ◽

Crescenzo D’Alterio ◽

Samantha Milanesi ◽

Alessandra Castagna ◽

Roberta Carriero ◽

...

Keyword(s):

Chemokine Receptors ◽

Cancer Biology ◽

Current Knowledge ◽

Chemotherapy Resistance ◽

Response To Therapy ◽

Aberrant Expression ◽

Molecular Alterations ◽

Whim Syndrome ◽

C Terminus ◽

Genomic Landscape

Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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Susceptibility of Avian Species to Brucella Infection: A Hypothesis-Driven Study

Pathogens ◽

10.3390/pathogens9020077 ◽

2020 ◽

Vol 9 (2) ◽

pp. 77 ◽

Cited By ~ 2

Author(s):

Gamal Wareth ◽

Ahmed Kheimar ◽

Heinrich Neubauer ◽

Falk Melzer

Keyword(s):

Experimental Infection ◽

Current Knowledge ◽

Empirical Studies ◽

Avian Species ◽

Diagnostic Tools ◽

Bacterial Disease ◽

Chicken Embryos ◽

Brucella Infection ◽

Wide Range

Brucellosis is a highly contagious bacterial disease affecting a wide range of animals, as well as humans. The existence of the clinically diagnosed brucellosis in avian species is controversially discussed. In the current study, we set to summarize the current knowledge on the presence of brucellae in avian species. Anti-Brucella antibodies were monitored in different avian species using classical diagnostic tools. Experimental infection of chicken embryos induced the disease and resulted in the development of specific lesions. Few empirical studies have been performed in adult poultry. However, the isolation of brucellae from naturally-infected chickens has not been possible yet.

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Placental imprinted gene expression mediates the effects of maternal psychosocial stress during pregnancy on fetal growth

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174418000545 ◽

2019 ◽

Vol 10 (02) ◽

pp. 196-205

Author(s):

L. Lambertini ◽

Q. Li ◽

Y. Ma ◽

W. Zhang ◽

K. Hao ◽

...

Keyword(s):

Gene Expression ◽

Fetal Growth ◽

Psychosocial Stress ◽

Imprinted Genes ◽

Economic Determinants ◽

Imprinted Gene ◽

Infant Gender ◽

Maternal Resources ◽

Gestational Age At Birth ◽

Lower Birthweight

AbstractImprinted genes uniquely drive and support fetoplacental growth by controlling the allocation of maternal resources to the fetus and affecting the newborn’s growth. We previously showed that alterations of the placental imprinted gene expression are associated with suboptimal perinatal growth and respond to environmental stimuli including socio-economic determinants. At the same time, maternal psychosocial stress during pregnancy (MPSP) has been shown to affect fetal growth. Here, we set out to test the hypothesis that placental imprinted gene expression mediates the effects of MPSP on fetal growth in a well-characterized birth cohort, the Stress in Pregnancy (SIP) Study. We observed that mothers experiencing high MPSP deliver infants with lower birthweight (P=0.047). Among the 109 imprinted genes tested, we detected panels of placental imprinted gene expression of 23 imprinted genes associated with MPSP and 26 with birthweight. Among these genes, five imprinted genes (CPXM2, glucosidase alpha acid (GAA), GPR1, SH3 and multiple ankyrin repeat domains 2 (SHANK2) and THSD7A) were common to the two panels. In multivariate analyses, controlling for maternal age and education and gestational age at birth and infant gender, two genes, GAA and SHANK2, each showed a 22% mediation of MPSP on fetal growth. These data provide new insights into the role that imprinted genes play in translating the maternal stress message into a fetoplacental growth pattern.

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Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-014-0278-0 ◽

2014 ◽

Vol 31 (10) ◽

pp. 1361-1368 ◽

Cited By ~ 31

Author(s):

Amilcar Cordeiro ◽

Ana Paula Neto ◽

Filipa Carvalho ◽

Carla Ramalho ◽

Sofia Dória

Keyword(s):

Genomic Imprinting ◽

Human Growth ◽

Imprinted Genes

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Growth and Development

Oxford Handbook of Evolutionary Medicine ◽

10.1093/oxfordhb/9780198789666.013.4 ◽

2019 ◽

pp. 129-166

Author(s):

Robin M. Bernstein ◽

Barry Bogin

Keyword(s):

Human Development ◽

Growth And Development ◽

Human Growth ◽

Postnatal Growth ◽

The Body ◽

Childhood And Adolescence ◽

Evolutionary Perspective ◽

Sociocultural Environment ◽

Human Growth And Development ◽

Biocultural Approach

An evolutionary and biocultural approach is taken to the study of human growth and development. The evolutionary perspective focuses on the unusual process of human postnatal growth and development, a process that takes two decades to complete and traverses the stages of infancy, childhood, juvenility, and adolescence. Human childhood and adolescence are highly unusual even compared to our closest living relatives, perhaps unique. The biocultural perspective of human development focuses on the constant interaction taking place during all phases of human development between genes and hormones within the body and the sociocultural environment that surrounds the body. While humans are often considered to be cooperative breeders, depending on social group helpers to successfully rear offspring, it may be more accurate to understand humans as practising biocultural reproduction as an adaptation to minimise risks to health.

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