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PLoS Genetics Dec 2020Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities,... (Review)
Review
Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal recessive loss-of-function mutation of the establishment of cohesion (ESCO) 2 acetyltransferase. ESCO2 is an essential gene that targets the DNA-binding cohesin complex. ESCO2 acetylates alternate subunits of cohesin to orchestrate vital cellular processes that include sister chromatid cohesion, chromosome condensation, transcription, and DNA repair. Although significant advances were made over the last 20 years in our understanding of ESCO2 and cohesin biology, the molecular etiology of RBS remains ambiguous. In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS.
Topics: Acetyltransferases; Animals; Chromosomal Proteins, Non-Histone; Craniofacial Abnormalities; DNA Damage; Ectromelia; Genomic Instability; Humans; Hypertelorism
PubMed: 33382686
DOI: 10.1371/journal.pgen.1009219 -
PloS One 2015Health monitoring is an integral part of laboratory animal quality standards. However, current or past prevalence data as well as regulatory requirements dictate the...
Health monitoring is an integral part of laboratory animal quality standards. However, current or past prevalence data as well as regulatory requirements dictate the frequency, type and the expanse of health monitoring. In an effort to understand the prevalence of rodent pathogens in India, a preliminary study was carried out by sero-epidemiology. Sera samples obtained from 26 public and private animal facilities were analyzed for the presence of antibodies against minute virus of mice (MVM), ectromelia virus (ECTV), lymphocytic choriomeningitis virus (LCMV), mouse hepatitis virus (MHV), Sendai virus (SeV), and Mycoplasma pulmonis in mice, and SeV, rat parvo virus (RPV), Kilham's rat virus (KRV) and sialodacryoadenitis virus (SDAV) in rats, by sandwich ELISA. It was observed that MHV was the most prevalent agent followed by Mycoplasma pulmonis and MVM in mice, and SDAV followed by RPV were prevalent in rats. On the other hand, none of the samples were positive for ECTV in mice, or SeV or KRV in rats. Multiple infections were common in both mice and rats. The incidence of MHV and Mycoplasma pulmonis was higher in facilities maintained by public organizations than in vivaria of private organizations, although the difference was not statistically different. On the other hand the prevalence of rodent pathogens was significantly higher in the northern part of India than in the South. These studies form the groundwork for detailed sero-prevalence studies which should further lay the foundations for country-specific guidelines for health monitoring of laboratory animals.
Topics: Animals; Animals, Laboratory; Antibodies, Bacterial; Antibodies, Viral; Enzyme-Linked Immunosorbent Assay; Geography; Incidence; India; Mice; Mycoplasma Infections; Mycoplasma pulmonis; Prevalence; Rats; Rodent Diseases; Seroepidemiologic Studies; Virus Diseases; Viruses
PubMed: 26158453
DOI: 10.1371/journal.pone.0131706 -
Journal of Virology Sep 2021Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control...
Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control ectromelia virus (ECTV) infection. How viral infections induce CD4-CTL responses remains incompletely understood. We demonstrate here that not only ECTV but also vaccinia virus and lymphocytic choriomeningitis virus induce CD4-CTL, though the response to ECTV is stronger. Using ECTV, we also demonstrate that in contrast to CD8-CTL, CD4-CTL differentiation requires constant virus replication and ceases once the virus is controlled. We also show that major histocompatibility complex class II molecules on CD11c cells are required for CD4-CTL differentiation and for mousepox resistance. Transcriptional analysis indicated that antiviral CD4-CTL and noncytolytic T helper 1 (Th1) CD4 T cells have similar transcriptional profiles, suggesting that CD4-CTL are terminally differentiated classical Th1 cells. Interestingly, CD4-CTL and classical Th1 cells expressed similar mRNA levels of the transcription factors ThPOK and GATA-3, necessary for CD4 T cell linage commitment, and Runx3, required for CD8 T cell development and effector function. However, at the protein level, CD4-CTL had higher levels of the three transcription factors, suggesting that further posttranscriptional regulation is required for CD4-CTL differentiation. Finally, CRISPR/Cas9-mediated deletion of in CD4 T cells inhibited CD4-CTL but not classical Th1 cell differentiation in response to ECTV infection. These results further our understanding of the mechanisms of CD4-CTL differentiation during viral infection and the role of posttranscriptionally regulated Runx3 in this process. While it is well established that cytotoxic CD4 T cells (CD4-CTLs) directly contribute to viral clearance, it remains unclear how CD4-CTL are induced. We now show that CD4-CTLs require sustained antigen presentation and are induced by CD11c-expressing antigen-presenting cells. Moreover, we show that CD4-CTLs are derived from the terminal differentiation of classical T helper 1 (Th1) subset of CD4 cells. Compared to Th1 cells, CD4-CTLs upregulate protein levels of the transcription factors ThPOK, Runx3, and GATA-3 posttranscriptionally. Deletion of Runx3 in differentiated CD4 T cells prevents induction of CD4-CTLs but not classical Th1 cells. These results advance our knowledge of how CD4-CTLs are induced during viral infection.
Topics: Animals; Antigen-Presenting Cells; CD11 Antigens; CD4-Positive T-Lymphocytes; Cell Differentiation; Core Binding Factor Alpha 3 Subunit; Cytotoxicity, Immunologic; Ectromelia virus; Ectromelia, Infectious; Histocompatibility Antigens Class II; Liver; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Spleen; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th1 Cells; Transcriptome; Virus Diseases; Virus Replication
PubMed: 34260270
DOI: 10.1128/JVI.00566-21 -
Proceedings of the National Academy of... Feb 2022Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are...
Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1β, IL-12p40, TGF-β, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cell Line; Chlorocebus aethiops; Cidofovir; Cytokines; Drug Evaluation, Preclinical; Drug Therapy, Combination; Ectromelia virus; Etanercept; Female; Lung; Mice, Inbred C57BL; NF-kappa B; Pneumonia, Viral; STAT3 Transcription Factor; Signal Transduction; Tumor Necrosis Factor-alpha; Viral Load; Mice
PubMed: 35177474
DOI: 10.1073/pnas.2112725119 -
Annals of the New York Academy of... Dec 2017Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia,... (Review)
Review
Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.
Topics: Ectromelia; Fibula; Genetic Predisposition to Disease; Humans; Limb Deformities, Congenital; Musculoskeletal Development; Mutation; Signal Transduction
PubMed: 28990185
DOI: 10.1111/nyas.13440 -
Translational Pediatrics Apr 2021Poland's syndrome (PS) is a rare musculoskeletal congenital anomaly with a wide spectrum of presentations. It is typically characterized by hypoplasia or aplasia of... (Review)
Review
Poland's syndrome (PS) is a rare musculoskeletal congenital anomaly with a wide spectrum of presentations. It is typically characterized by hypoplasia or aplasia of pectoral muscles, mammary hypoplasia and variably associated ipsilateral limb anomalies. Limb defects can vary in severity, ranging from syndactyly to phocomelia. Most cases are sporadic but familial cases with intrafamilial variability have been reported. Several theories have been proposed regarding the genesis of PS. Vascular disruption theory, "the subclavian artery supply disruption sequence" (SASDS) remains the most accepted pathogenic mechanism. Clinical presentations can vary in severity from syndactyly to phocomelia in the limbs and in the thorax, rib defects to severe chest wall anomalies with impaired lung function. Most patients have subtle presentation at birth and milder forms in childhood. Functional limitations due to PS are usually minimal. Surgical treatment aims to improve pulmonary functions arising from severe thoracic deformities but is more often done to enhance the cosmesis. The use of adipose-derived mesenchymal stem cells and fat transfer have shown promising results in recent times for correction of chest defects and breast augmentation. Gaining deeper insights into the etiopathogenesis and clinical presentation of PS will improve the clinical recognition and management of this rare condition. In this review article, we aim to outline the details of this syndrome including its etiopathogenesis, evolution, spectrum of clinical manifestations, other systemic associations, diagnostic modalities, and recent advances in treatment.
PubMed: 34012849
DOI: 10.21037/tp-20-320 -
Molecular Genetics & Genomic Medicine Jun 2023Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene....
OBJECTIVE
Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene. Cardinal clinical manifestations are pre- and postnatal growth retardation and craniofacial and limb malformations. Here, we report RBS in a Chinese adolescent with novel biallelic ESCO2 variations and complex cerebrovascular diseases.
METHODS
Medical history, neurological examinations, neuroimaging, and pathology were collected in the proband and the family. Whole exome sequencing (WES) with copy number variation analysis was performed to screen for genetic variations.
RESULTS
The clinical features of the proband were craniofacial and limb malformations together with complex cerebrovascular diseases. She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old. Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts. Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy. Whole exome sequencing (WES) identified novel biallelic variations in the ESCO2 gene (c.1220A>T, p.H407L and c.1562delC, p.A521fs).
CONCLUSIONS
We describe complex cerebrovascular diseases in Roberts syndrome caused by novel ESCO2 biallelic variations. This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts.
Topics: Craniofacial Abnormalities; Humans; Female; Adolescent; Acetyltransferases; Chromosomal Proteins, Non-Histone; East Asian People; Cerebrovascular Disorders
PubMed: 37002187
DOI: 10.1002/mgg3.2177 -
SAGE Open Medical Case Reports 2023The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors...
The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors present a case of phocomelia caused by thalidomide with end-stage osteoarthritis and grossly medialized patella. The patient was treated with a cemented constrained non-hinged prosthesis and patelloplasty. Six months later, the patient had complete relief of pain and was able to walk without walking assistance. To our knowledge, total knee replacement in a patient with phocomelia caused by thalidomide has not been described in literature.
PubMed: 36798679
DOI: 10.1177/2050313X231154635 -
Medicine Dec 2018Sirenomelia is a very rare congenital malformation and characterized by fused lower extremities, oligohydramnios, renal agenesis, absent urinary tract and external... (Review)
Review
RATIONALE
Sirenomelia is a very rare congenital malformation and characterized by fused lower extremities, oligohydramnios, renal agenesis, absent urinary tract and external genitalia, single umbilical artery, and imperforate anus. Ultrasonography is an optimal method for prenatal screening and diagnosis of sirenomelia. The incidence of sirenomelia in the twin pregnancy is extremely low.
PATIENT CONCERNS
We reported a case of 1 twin with sirenomelia in dichorionic-diamniotic twin pregnancy after in vitro fertilization and embryo transfer.
DIAGNOSES
The sirenomelia twin was diagnosed at the 2nd trimester by ultrasonic examination and complicated with oligohydramnios and a single umbilical artery, another twin was normal.
INTERVENTIONS
A regular and careful antenatal care was conducted. The parents refused to examine the chromosome of sirenomelia twin, and the chromosomal microarray analysis of the amniotic fluid sample was only achieved in the normal anatomy twin after extensively counseled by the multi-disciplinary team.
OUTCOMES
At 34+2 gestational weeks, the demise of the malformed twin occurred, while fetal heart rate monitoring of the normal twin was abnormal, and an emergency cesarean section was performed. A healthy male baby was delivered with Apgar scores of 10 and 10 at 1 and 5 minutes, respectively. The mother and the baby were followed up and are in good health until now.
CONCLUSION
Sirenomelia is a lethal condition in the perinatal period. Early antenatal diagnosis is very important. Voluntary selective termination of sirenomelia 1 in twin pregnancy may be advised. Expecting parents should be counseled by the multidisciplinary team about the management and prognosis of the sirenomelia.
Topics: Abortion, Spontaneous; Adult; Diseases in Twins; Ectromelia; Embryo Transfer; Fatal Outcome; Female; Fertilization in Vitro; Humans; Infant, Newborn; Male; Oligohydramnios; Pregnancy; Pregnancy, Twin; Ultrasonography, Prenatal
PubMed: 30572488
DOI: 10.1097/MD.0000000000013672 -
Viruses Aug 2017Taterapox virus (TATV), which was isolated from an African gerbil () in 1975, is the most closely related virus to variola; however, only the original report has...
Taterapox virus (TATV), which was isolated from an African gerbil () in 1975, is the most closely related virus to variola; however, only the original report has examined its virology. We have evaluated the tropism of TATV in vivo in small animals. We found that TATV does not infect , a species of African dormouse, but does induce seroconversion in the Mongolian gerbil () and in mice; however, in wild-type mice and gerbils, the virus produces an unapparent infection. Following intranasal and footpad inoculations with 1 × 10⁶ plaque forming units (PFU) of TATV, immunocompromised mice showed signs of disease but did not die; however, SCID mice were susceptible to intranasal and footpad infections with 100% mortality observed by Day 35 and Day 54, respectively. We show that death is unlikely to be a result of the virus mutating to have increased virulence and that SCID mice are capable of transmitting TATV to C57BL/6 and C57BL/6 animals; however, transmission did not occur from TATV inoculated wild-type or mice. Comparisons with ectromelia (the etiological agent of mousepox) suggest that TATV behaves differently both at the site of inoculation and in the immune response that it triggers.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Ectromelia virus; Ectromelia, Infectious; Host Specificity; Mice; Mice, Inbred C57BL; Mice, SCID; Orthopoxvirus; Poxviridae Infections; STAT1 Transcription Factor; Viral Tropism
PubMed: 28763036
DOI: 10.3390/v9080203