scholarly journals Phenotypes, Developmental Basis, and Genetics of Pierre Robin Complex

2020 ◽  
Vol 8 (4) ◽  
pp. 30
Author(s):  
Susan M. Motch Perrine ◽  
Meng Wu ◽  
Greg Holmes ◽  
Bryan C. Bjork ◽  
Ethylin Wang Jabs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Models ◽  
Cleft Palate ◽  
Phenotypic Variation ◽  
Genetic Variants ◽  
Genetic Basis ◽  
Associated Anomalies ◽  
Respiratory Obstruction ◽  
Cellular Processes ◽  
Pierre Robin

The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory obstruction, and in some cases, cleft palate. A causative sequence of developmental events is hypothesized for PR, but few clear causal relationships between discovered genetic variants, dysregulated gene expression, precise cellular processes, pathogenesis, and PR-associated anomalies are documented. This review presents the current understanding of PR phenotypes, the proposed pathogenetic processes underlying them, select genes associated with PR, and available animal models that could be used to better understand the genetic basis and phenotypic variation of PR.

scholarly journals Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate

2020 ◽  
Vol 99 (13) ◽  
pp. 1461-1468
Author(s):  
M. He ◽  
X. Zuo ◽  
H. Liu ◽  
W. Wang ◽  
Y. Zhang ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Embryonic Patterning ◽  
Chinese Han ◽  
Cellular Processes ◽  
Risk Alleles ◽  
Genome Wide ◽  
Genome Wide Significance

The 3 major subphenotypes observed in patients with nonsyndromic orofacial clefts (NSOFCs) are nonsyndromic cleft lip only (NSCLO), nonsyndromic cleft lip with palate (NSCLP), and nonsyndromic cleft palate only (NSCPO). However, the genetic architecture underlying NSCPO is largely unknown. Here we performed a 2-stage genome-wide association study (GWAS) on NSCPO and replication analyses of selected variants in other NSOFCs from the Chinese Han population. We identified a novel locus (15q24.3) and a known locus (1q32.2) where variants in or near the gene reached genome-wide significance (2.80 × 10−13 < P < 1.72 × 10−08) in a test for association with NSCPO in a case-control design. Although a variant from 15q24.3 was found to be significantly associated with both NSCPO and NSCLP, the direction of estimated effects on risk were opposite. Our functional annotation of the risk alleles within 15q24.3 coupled with previously established roles of the candidate genes within identified risk loci in periderm development, embryonic patterning, and/or regulation of cellular processes supports their involvement in palate development and the pathogenesis of cleft palate. Our study advances the understanding of the genetic basis of NSOFCs and provides novel insights into the pathogenesis of NSCPO.

scholarly journals Cleft palate in Pierre Robin sequence

2021 ◽  
Vol 319 ◽  
pp. 02013
Author(s):  
Houda Oubejja ◽  
Imane Menbahi ◽  
Chadi Elhasnaoui ◽  
Souha Qurouach ◽  
Ismail Benomar ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Functional Results ◽  
Pierre Robin Sequence ◽  
Children And Families ◽  
Respiratory Obstruction ◽  
Surgical Emergencies ◽  
Female Predominance ◽  
Upper Respiratory ◽  
Pierre Robin

Pierre Robin’s sequence PRS is a congenital malformative sequence with a retrognathism, a glossoptosis and an upper respiratory obstruction with an associated cleft palate. This malformative association can be disabling for both the child and his parents, because of its aesthetic, functional, psychological and social impacts. Patients and methods: We have investigated 14 patients with PRS presenting cleft palates, collected over a period of 5 years, from March 2014 to November 2019 in the pediatric surgical emergencies department (PSE) in Rabat Children’s Hospital (HER). Results: Nine of the 14 patients had a complete cleft palate. The average age of intervention was 23 months ranging from 13 months to 4 years. The study showed a slight female predominance (n = 8, 57%). Regarding the treatment, 3 patients were treated with the Bardach’s technique, 3 had the Von Langenbeck’s technique, 3 had the Push-back technique and one patient who suffered from a post-operative persisting velar division was treated by veloplasty 3rd generation. The hospital stay was around 24 hours and the post-operative follow-up was uncomplicated for all our patients. Conclusion: Although we had a relatively high success with our approach, the complexity and lack of consensus regarding the management of Pierre Robin’s sequence still requires the involvement of a multidisciplinary team. The main aim is to give the best aesthetical and functional results in order to reduce the suffering of the PRS children and families.

scholarly journals Genetic architecture of root and shoot ionomes in rice (Oryza sativa L.)

2021 ◽  
Author(s):  
Joshua N. Cobb ◽  
Chen Chen ◽  
Yuxin Shi ◽  
Lyza G. Maron ◽  
Danni Liu ◽  
...  
Keyword(s):  
Oryza Sativa ◽  
Candidate Genes ◽  
Association Analysis ◽  
Phenotypic Variation ◽  
Genetic Variants ◽  
Genetic Basis ◽  
Living Environment ◽  
Mineral Nutrient ◽  
Genome Wide ◽  
Genomic Regions

Abstract Key message Association analysis for ionomic concentrations of 20 elements identified independent genetic factors underlying the root and shoot ionomes of rice, providing a platform for selecting and dissecting causal genetic variants. Abstract Understanding the genetic basis of mineral nutrient acquisition is key to fully describing how terrestrial organisms interact with the non-living environment. Rice (Oryza sativa L.) serves both as a model organism for genetic studies and as an important component of the global food system. Studies in rice ionomics have primarily focused on above ground tissues evaluated from field-grown plants. Here, we describe a comprehensive study of the genetic basis of the rice ionome in both roots and shoots of 6-week-old rice plants for 20 elements using a controlled hydroponics growth system. Building on the wealth of publicly available rice genomic resources, including a panel of 373 diverse rice lines, 4.8 M genome-wide single-nucleotide polymorphisms, single- and multi-marker analysis pipelines, an extensive tome of 321 candidate genes and legacy QTLs from across 15 years of rice genetics literature, we used genome-wide association analysis and biparental QTL analysis to identify 114 genomic regions associated with ionomic variation. The genetic basis for root and shoot ionomes was highly distinct; 78 loci were associated with roots and 36 loci with shoots, with no overlapping genomic regions for the same element across tissues. We further describe the distribution of phenotypic variation across haplotypes and identify candidate genes within highly significant regions associated with sulfur, manganese, cadmium, and molybdenum. Our analysis provides critical insight into the genetic basis of natural phenotypic variation for both root and shoot ionomes in rice and provides a comprehensive resource for dissecting and testing causal genetic variants.

scholarly journals Epistatic interactions of genetic loci associated with age-related macular degeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christina Kiel ◽  
Christoph A. Nebauer ◽  
Tobias Strunz ◽  
Simon Stelzl ◽  
Bernhard H. F. Weber
Keyword(s):  
Gene Expression ◽  
Macular Degeneration ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Age Related Macular Degeneration ◽  
Risk Scores ◽  
Cellular Processes ◽  
Age Related ◽  
Genome Wide ◽  
Extracellular Structures

AbstractThe currently largest genome-wide association study (GWAS) for age-related macular degeneration (AMD) defines disease association with genome-wide significance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD-associated variants that reveal joint effects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifically the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high-risk AMD. We identified genetic variant combinations correlating significantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defines novel targets and allows prioritizing further functional work into AMD pathobiology.

The Genetic Basis of the Pierre Robin Sequence

2006 ◽  
Vol 43 (2) ◽  
pp. 155-159 ◽  
Author(s):  
Linda P. Jakobsen ◽  
Mary A. Knudsen ◽  
James Lespinasse ◽  
Carmen García Ayuso ◽  
Carmen Ramos ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Candidate Genes ◽  
Cleft Lip ◽  
Genetic Basis ◽  
Mendelian Inheritance ◽  
Potential Candidate ◽  
Pierre Robin Sequence ◽  
Gene Map ◽  
Robin Sequence ◽  
Pierre Robin

Objective The Pierre Robin Sequence (PRS) is subgroup of the cleft palate population. As with the etiology of cleft lip or palate, the etiology of PRS is generally unknown. Some factors are suggestive of a genetic basis for PRS. The purpose of this study was to compare genetic information on PRS available in the literature and in a cytogenetic database to facilitate focused genetic studies of PRS. Design After searching Medline for “pierre robin and genetics,” the Mendelian Cytogenetics Network database for “robin” and “pierre robin,” and two reviews from the Human Cytogenetics Database for “cleft palate” and “micrognathia,” a comparison of the data and a search in Online Mendelian Inheritance in Man (OMIM) Gene Map was performed to identify relevant candidate genes. Results The findings revealed consistency to a certain degree to loci 2q24.1-33.3, 4q32-qter, 11q21-23.1, and 17q21-24.3. A search in the OMIM Gene Map provided many candidate genes for PRS in these regions. The GAD67 on 2q31, the PVRL1 on 11q23-q24, and the SOX9 gene on 17q24.3-q25.1 are suggested to be of particular importance. Conclusion Candidate loci and a few potential candidate genes for PRS are proposed from the present study. This may enable researchers to focus their effort in the studies of PRS.

scholarly journals Rare Genetic Variants Underlie Outlying levels of DNA Methylation and Gene-Expression

2020 ◽  
Author(s):  
V. Kartik Chundru ◽  
Riccardo E. Marioni ◽  
James G. D. Pendergast ◽  
Tian Lin ◽  
Allan J. Beveridge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Phenotypic Variation ◽  
Genetic Variants ◽  
Rare Variants ◽  
Effect Sizes ◽  
Expression Levels ◽  
Low Level ◽  
Rare Genetic Variants ◽  
Gene Expression Levels

AbstractTesting the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on low-level genomic traits, such as gene expression or DNA methylation (DNAm), as effect sizes are expected to be larger for low-level compared to higher-order complex traits. Here, we investigate DNAm in healthy ageing populations - the Lothian Birth cohorts of 1921 and 1936 and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic variants within 1kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels towards the tails of the population distribution. Overall, this study demonstrates the role of rare variants in the phenotypic variation of low-level genomic traits, and the effect of extreme levels of DNAm on gene expression.

scholarly journals Comprehensive Genome-Wide Association Analysis Reveals the Genetic Basis of Root System Architecture in Soybean

2020 ◽  
Vol 11 ◽  
Author(s):  
Waldiodio Seck ◽  
Davoud Torkamaneh ◽  
François Belzile
Keyword(s):  
Root System ◽  
System Architecture ◽  
Phenotypic Variation ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Primary Root ◽  
Root System Architecture ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

Increasing the understanding genetic basis of the variability in root system architecture (RSA) is essential to improve resource-use efficiency in agriculture systems and to develop climate-resilient crop cultivars. Roots being underground, their direct observation and detailed characterization are challenging. Here, were characterized twelve RSA-related traits in a panel of 137 early maturing soybean lines (Canadian soybean core collection) using rhizoboxes and two-dimensional imaging. Significant phenotypic variation (P &lt; 0.001) was observed among these lines for different RSA-related traits. This panel was genotyped with 2.18 million genome-wide single-nucleotide polymorphisms (SNPs) using a combination of genotyping-by-sequencing and whole-genome sequencing. A total of 10 quantitative trait locus (QTL) regions were detected for root total length and primary root diameter through a comprehensive genome-wide association study. These QTL regions explained from 15 to 25% of the phenotypic variation and contained two putative candidate genes with homology to genes previously reported to play a role in RSA in other species. These genes can serve to accelerate future efforts aimed to dissect genetic architecture of RSA and breed more resilient varieties.

scholarly journals Mitochondrial Glucocorticoid Receptors and Their Actions

2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptors ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Ros Generation ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Energy Metabolism ◽  
Bcl2 Family ◽  
Cellular Processes ◽  
Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

scholarly journals OP0045 NLRP12 INVOLVES IN THE LUPUS WITH POSITIVE INTERFERON SIGNATURE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 23.2-24
Author(s):  
Y. P. Tsao ◽  
F. Y. Tseng ◽  
C. W. Chao ◽  
M. H. Chen ◽  
S. T. Chen
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Animal Models ◽  
Nucleic Acids ◽  
Disease Activity ◽  
Interferon Signature ◽  
Healthy Donors ◽  
Healthy Control ◽  
Lupus Disease Activity

Background:Systemic lupus erythematous (SLE) is a systemic autoimmune disease with diverse etiological factors. It was recognized that interferon (IFN) signature involved in the progress of SLE. NLRP12 (NOD-like receptor family (NLR) pyrin domain containing 12) is a pyrin containing NLR protein that we had linked its new biological function to the cross-regulation of Toll like receptor (TLRs) and Rig-I like receptor (RIG-I) pathways. NLPR12 acts as an innate immune check-point in regulating type I IFNs expression during TLRs and RIG-I activation. The importance of NLRP12 in lupus disease activity remained to be elucidated.Objectives:To clarify the role of NLRP12 in regulating the interferon signature.Methods:Peripheral blood mononuclear cells (PBMCs) were collected from SLE patients and healthy donors for analysis of NLRP12 and IFN-α gene expression by RT-QPCR. PBMCs were applied for Chromatin immuneprecipitation (ChIP) assay and electrical mobility shift assay (EMSA) to determine the putative transcription factor that regulates NLRP12 expression. An involvement of epigenetic regulation of NLRP12 expression in SLE patients was also analyzed. Bone marrow derived dendritic cells (BMDCs) were collected from wild type mouse and Nlrp12 knocked-out mice. Another CD14+ monocytes were isolated from 10 cases of lupus patients and 8 cases of healthy control, following by stimulating different type of nucleic acids, and IFN-α and IL-6 were measured with ELISA assay. CD14+ monocytes in lupus patients were also pre-treated with IFNAR2 antibody for further nucleic acid stimulation. Two mice models were applied for evaluation the role of Nlrp12: intraperitoneal injection of TMPD (2,6,10,14-tetramethylpentadecane, or pristane) in C57BL/6 mice and Faslpr mice. Both models were conducted with and without Nlrp12 knockout.Results:NLRP12 expression was significantly lower in PBMC isolated from SLE patients compared to healthy donors. The inverse correlation was observed in NLRP12 and IFNA gene expression as well as NLRP12 expression and amount of double-stranded DNA autoantibody in SLE patients. NLRP12 expression showed negative correlations with IFN-α treatment, as well as herpes simplex virus-1 (HSV-1) infection. Results from ChIP and EMSA analysis indicated a potential transcription factor 1 (TF-1) regulating NLRP12 promoter activity. TF-1 lead to transcriptional suppression of NLRP12 in SLE PBMC, and it was gradually induced after IFN treatment. Recruitment of TF-1 to NLRP12 promoter in SLE PBMC compared to the healthy PBMC was detected, and increased when treating with IFN. Human CD14+ monocytes collected from lupus and healthy control stimulating with different type of nucleic acids revealing significant increasing level of IFN-α and IL-6 in lupus patients. Among animal models, both pristine induced mice and Faslpr mice revealed increasing autoantibodies production and severity of glomerulonephritis in Nlrp12-/- group in comparison with Nlrp12+/+ ones, indicating the role of NLRP12 in maintaining positive interferon signature as well as disease activity.Conclusion:Expression level of NLRP1.2 has been demonstrated to be a biomarker of disease activity in SLE patients. The NLRP12 was involved in the interferon signature, which was also negatively regulated by TF-1. Both clinical samples and animal models revealed NLRP12 in maintaining the positive interferon signature, indicating the possible role of exacerbating factor for lupus disease activity.Disclosure of Interests:None declared

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