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European Journal of Medical Genetics Apr 2020To investigate whether increased parental age is associated with an increased risk for de novo copy number variant (CNV) formation in offspring.
PURPOSE
To investigate whether increased parental age is associated with an increased risk for de novo copy number variant (CNV) formation in offspring.
METHODS
CNV calls from 2323 individuals referred to Signature Genomic Laboratories for clinical microarray-based comparative genomic hybridization were investigated; 17% of the samples were prenatal and 83% were postnatal. The de novo CNV data were further split into de novo CNVs bound by low copy repeats (LCRs) and those not bound by LCRs.
RESULTS
No association was found between CNV occurrence and paternal age in both the prenatal (p = 0.6795) and postnatal (p = 0.1741) cohorts. Maternal age was significantly higher with de novo CNV occurrence in our postnatal cohort (p = 0.0126), an effect which may be driven by formation of de novo CNVs that are bound by LCRs (p = 0.0026). Furthermore, a significant positive correlation was observed between maternal age and de novo CNVs (Point-Biserial R = 0.0503, p = 0.0152).
CONCLUSIONS
This large-scale study did not find any evidence for the influence of increased paternal age on de novo CNV formation, while increased maternal age appeared to increase risk for de novo, non-complex CNV occurrence in offspring with intellectual disability/developmental delay. Further studies and continued technological advances will help yield more information on the risk factors for de novo CNVs.
Topics: Adult; DNA Copy Number Variations; Fathers; Female; Humans; Infant, Newborn; Male; Mothers; Parents
PubMed: 31883480
DOI: 10.1016/j.ejmg.2019.103829 -
Trends in Genetics : TIG Nov 2019DNA methylation regulates the organization and function of the genome. Yamanaka et al. now report that de novo methylation of male germ cells of mice involves the...
DNA methylation regulates the organization and function of the genome. Yamanaka et al. now report that de novo methylation of male germ cells of mice involves the transient opening of heterochromatin at megabase-size differentially accessible domains (DADs). This chromatin remodeling likely facilitates de novo methylation of the germ cell genome.
Topics: Animals; Chromatin; DNA Methylation; Genome; Germ Cells; Heterochromatin; Male; Mice
PubMed: 31597610
DOI: 10.1016/j.tig.2019.09.001 -
Journal of Clinical and Experimental... 2020Liver transplantation (LT) recipients such as all organ transplant recipients, have a risk of developing de novo malignancies owing to prolonged immunosuppression....
BACKGROUND AND AIMS
Liver transplantation (LT) recipients such as all organ transplant recipients, have a risk of developing de novo malignancies owing to prolonged immunosuppression. However, there is limited data on this after living donor liver transplantation (LDLT), wherein immunosuppression levels are less than in deceased donor transplantation. We aim to describe experience of de novo malignancies from a predominantly LDLT center.
MATERIALS AND METHODS
A total of 2100 adults (age >18 years) who underwent LT between January 2006 and December 2017 were retrospectively analyzed from a prospectively collected database. The data were analyzed up to June 2019. Data are shown as number, percentage, mean ± standard deviation, and median (interquartile range).
RESULTS
Of 2100 patients who underwent LDLT, 21 (1%) patients developed de novo malignancy after transplantation. The de novo malignancy cohort comprised 20 males and 1 female, aged 50 ± 8.8 years. The distribution of de novo malignancies was as follows: 7 oropharyngeal (carcinoma of buccal and oral mucosa), 4 lung, 2 squamous cell carcinoma of skin, 2 lymphoma, 1 each of brain, colonic, gastric; ovary, pancreatic, and prostate. These malignancies were diagnosed at a median follow-up of 42 months (32-73) after LT. Over a median follow-up of 38 months (10-56) after the diagnosis of de novo malignancy, 6 patients (28.5%) died. Patients with de novo malignancy had a higher follow-up after LDLT, 94.3 ± 32.9 versus 62.5 ± 41.8 months, = 0.000. Patients with alcohol as etiology for LT had higher trend of de novo malignancies (33.3% versus 26.4%), = 0.46.
CONCLUSION
The incidence of de novo malignancy was 1% at a median follow-up of 42 (32-73) months. De novo malignancies following LDLT, although uncommon, are associated with significant mortality. A careful screening protocol should be followed after transplantation for early detection of de novo malignancies.
PubMed: 33029053
DOI: 10.1016/j.jceh.2020.02.001 -
Pathology Oncology Research : POR Oct 2020The clinical significances of de novo and nevus-associated melanomas are controversial. In this study, we investigated the correlations of these forms of melanomas in...
The clinical significances of de novo and nevus-associated melanomas are controversial. In this study, we investigated the correlations of these forms of melanomas in respect to their pathological and clinical features and patient outcomes. The data of 660 pathologically confirmed Turkish-Caucasian melanoma patients, whose tumors were either associated with a pre-existing melanocytic nevus or not, were analyzed retrospectively. They were treated and followed up at a single tertiary referral center. A total of 440 de novo (66.7%) and 220 nevus-associated melanomas (33.3%) were enrolled into the study. The median age of the patients was 51 years. The patients consisted of 341 men (51.7%) and 319 women (48.3%). There were significant correlations between de novo melanomas and advanced age (p = 0.003), tumor thickness greater than 2 mm (p = 0.0001), ulceration (p = 0.01) and high mitotic rate (p = 0.03). On the other hand, nevus-associated melanomas were found significantly associated with histological regression (p = 0.03) and BRAFV600E mutation (p = 0.003). Most of the nevus-associated melanomas were found on trunk and head/neck, whereas extremities were more frequently inflicted by de novo melanomas (p = 0.0001). Furthermore, none of other variables, such as sex, histopathology, lymph node involvement and presence of metastasis, showed statistically significant difference between de novo and nevus-associated melanoma patients (p > 0.05). The 5-year DFS rates were 62.4% and 72.7% for de novo melanoma and for nevus-associated melanoma patients, respectively (p = 0.1). The 5-year OS rate were 72.1% and 76.4% for de novo melanoma and nevus-associated melanoma patients, respectively (p = 0.2). In conclusion, even though de novo melanomas are more significantly correlated with aggressive histopathologic variables, such as tumor depth, ulceration and high mitotic rate, the survival rates of de novo and nevus-associated melanomas are similar.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Disease-Free Survival; Female; Humans; Male; Melanoma; Middle Aged; Nevus, Pigmented; Prognosis; Retrospective Studies; Skin Neoplasms; Young Adult
PubMed: 32572820
DOI: 10.1007/s12253-020-00858-4 -
PLoS Neglected Tropical Diseases Apr 2017Trypanosomatid parasites, including Trypanosoma and Leishmania, are the causative agents of lethal diseases threatening millions of people around the world. These... (Review)
Review
Trypanosomatid parasites, including Trypanosoma and Leishmania, are the causative agents of lethal diseases threatening millions of people around the world. These organisms compartmentalize glycolysis in essential, specialized peroxisomes called glycosomes. Peroxisome proliferation can occur through growth and division of existing organelles and de novo biogenesis from the endoplasmic reticulum. The level that each pathway contributes is debated. Current evidence supports the concerted contribution of both mechanisms in an equilibrium that can vary depending on environmental conditions and metabolic requirements of the cell. Homologs of a number of peroxins, the proteins involved in peroxisome biogenesis and matrix protein import, have been identified in T. brucei. Based on these findings, it is widely accepted that glycosomes proliferate through growth and division of existing organelles; however, to our knowledge, a de novo mechanism of biogenesis has not been directly demonstrated. Here, we review recent findings that provide support for the existence of an endoplasmic reticulum (ER)-derived de novo pathway of glycosome biogenesis in T. brucei. Two studies recently identified PEX13.1, a peroxin involved in matrix protein import, in the ER of procyclic form T. brucei. In other eukaryotes, peroxins including PEX13 have been found in the ER of cells undergoing de novo biogenesis of peroxisomes. In addition, PEX16 and PEX19 have been characterized in T. brucei, both of which are important for de novo biogenesis in other eukaryotes. Because glycosomes are rapidly remodeled via autophagy during life cycle differentiation, de novo biogenesis could provide a method of restoring glycosome populations following turnover. Together, the findings we summarize provide support for the hypothesis that glycosome proliferation occurs through growth and division of pre-existing organelles and de novo biogenesis of new organelles from the ER and that the level each mechanism contributes is influenced by glucose availability.
Topics: Autophagy; Cell Differentiation; Endoplasmic Reticulum; Leishmania; Life Cycle Stages; Membrane Proteins; Microbodies; Peroxisomes; Protozoan Proteins; Trypanosoma brucei brucei
PubMed: 28426655
DOI: 10.1371/journal.pntd.0005333 -
Autoimmune hepatitis and liver transplantation: Indications, and recurrent and autoimmune hepatitis.World Journal of Transplantation Mar 2022Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver... (Review)
Review
Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver transplantation may be required for patients with acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Recurrence is defined as development of the same disease in the allograft following liver transplantation. Autoimmune hepatitis recurs in 36%-68% of the recipients 5 years after liver transplantation. autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis. Diagnostic work up for recurrent and autoimmune hepatitis is similar to the diagnosis of the original disease, and it is usually difficult. Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and autoimmune hepatitis. Early diagnosis and treatment are vital for patient prognosis because autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.
PubMed: 35433333
DOI: 10.5500/wjt.v12.i3.59 -
International Urogynecology Journal Feb 2020To investigate the prevalence and risk factors of de novo urinary incontinence (UI) after pelvic organ prolapse (POP) surgery.
INTRODUCTION AND HYPOTHESIS
To investigate the prevalence and risk factors of de novo urinary incontinence (UI) after pelvic organ prolapse (POP) surgery.
METHODS
Data from 2013 to 2016 were collected from the Danish Urogynecological Database, where registration for any urogynecological procedure performed in Denmark is mandatory. Inclusion criteria were urinary continent women who underwent POP surgery. A woman was urinary continent if her total score on the International Consultation on Incontinence Questionnaire-Urinary Incontinence-short form (ICIQ-UI-sf) was 0 and she answered 'never' to 'When does urine leak?' Postoperatively, the women were categorized as continent or women with stress urinary incontinence (SUI), urgency urinary incontinence (UUI), mixed urinary incontinence (MUI) or undefined UI. We performed multivariate logistic regression analyses. The included parameters were preoperative POP stage (POP-Q), compartment, BMI and age. P values < 0.05 were considered statistically significant.
RESULTS
We included 1198 women. The risk of de novo UI was 15%; 45% had SUI, 30% had UUI, 16% had MUI, and 10% had undefined UI. BMI was highly associated with de novo UI; the risk was 12% for women with BMI < 25, 16% for women with BMI 25 - < 30 and 23% for women with BMI ≥ 30. Age, compartment and POP stage were not associated with de novo UI.
CONCLUSIONS
The prevalence of de novo UI is the same regardless of the involved compartment/s and POP stage. BMI is significantly associated with de novo UI; twice as many women with BMI ≥ 30 had de novo UI compared with women with BMI < 25.
Topics: Aged; Body Mass Index; Databases, Factual; Denmark; Female; Humans; Middle Aged; Pelvic Organ Prolapse; Postoperative Complications; Postoperative Period; Prevalence; Plastic Surgery Procedures; Risk Factors; Urinary Incontinence
PubMed: 31302717
DOI: 10.1007/s00192-019-04041-5 -
Proceedings of the National Academy of... Oct 2022De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test...
De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test for our understanding of the underlying physical principles of protein folding and may lead to the development of proteins with unmatched functional characteristics. The first fundamental challenge of de novo design is to devise "designable" structural templates leading to sequences that will adopt the predicted fold. Here, we built on the TopoBuilder (TB) de novo design method, to automatically assemble structural templates with native-like features starting from string descriptors that capture the overall topology of proteins. Our framework eliminates the dependency of hand-crafted and fold-specific rules through an iterative, data-driven approach that extracts geometrical parameters from structural tertiary motifs. We evaluated the TopoBuilder framework by designing sequences for a set of five protein folds and experimental characterization revealed that several sequences were folded and stable in solution. The TopoBuilder de novo design framework will be broadly useful to guide the generation of artificial proteins with customized geometries, enabling the exploration of the protein universe.
Topics: Models, Molecular; Protein Engineering; Protein Folding; Proteins
PubMed: 36252041
DOI: 10.1073/pnas.2206111119 -
Nature Ecology & Evolution Apr 2023De novo gene emergence provides a route for new proteins to be formed from previously non-coding DNA. Proteins born in this way are considered random sequences and...
De novo gene emergence provides a route for new proteins to be formed from previously non-coding DNA. Proteins born in this way are considered random sequences and typically assumed to lack defined structure. While it remains unclear how likely a de novo protein is to assume a soluble and stable tertiary structure, intersecting evidence from random sequence and de novo-designed proteins suggests that native-like biophysical properties are abundant in sequence space. Taking putative de novo proteins identified in human and fly, we experimentally characterize a library of these sequences to assess their solubility and structure propensity. We compare this library to a set of synthetic random proteins with no evolutionary history. Bioinformatic prediction suggests that de novo proteins may have remarkably similar distributions of biophysical properties to unevolved random sequences of a given length and amino acid composition. However, upon expression in vitro, de novo proteins exhibit moderately higher solubility which is further induced by the DnaK chaperone system. We suggest that while synthetic random sequences are a useful proxy for de novo proteins in terms of structure propensity, de novo proteins may be better integrated in the cellular system than random expectation, given their higher solubility.
Topics: Humans; Proteins; Proteomics; Computational Biology
PubMed: 37024625
DOI: 10.1038/s41559-023-02010-2 -
Molecular Genetics & Genomic Medicine Sep 2019De novo likely gene-disrupting variants of POGZ cause autism spectrum disorder (ASD) and intellectual disability. However, de novo missense variants of this gene were...
BACKGROUND
De novo likely gene-disrupting variants of POGZ cause autism spectrum disorder (ASD) and intellectual disability. However, de novo missense variants of this gene were not well explored in neuropsychiatric disorders.
METHODS
The single-molecule molecular inversion probes-based targeted sequencing method was performed on the proband. Variant was validated using Sanger sequencing in both proband and parents. Immunoblot analysis was performed to examine the expression of POGZ in patient-derived peripheral blood lymphocytes. Published POGZ de novo missense variants in neuropsychiatric disorders were reviewed.
RESULTS
We detected a novel de novo missense variant in POGZ (c.1534C>A, p.H512N, NM_015100.4) in an individual with ASD. Immunoblot analysis revealed a dramatic reduction in POGZ protein in patient-derived peripheral blood lymphocytes suggesting a loss-of-function mechanism of this de novo missense variant. In addition, we collected and annotated additional eight POGZ de novo missense variants identified in neuropsychiatric disorders from literatures.
CONCLUSION
Our findings will be beneficial to the functional analysis of POGZ in ASD pathogenesis, and for genetic counseling and clinical diagnosis of patients with POGZ de novo missense variants.
Topics: Asian People; Autism Spectrum Disorder; Child Behavior; Child, Preschool; Female; Humans; Intellectual Disability; Lymphocytes; Male; Mutation, Missense; Phenotype; Transposases
PubMed: 31347273
DOI: 10.1002/mgg3.900