scholarly journals De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome

2022 ◽  
Vol 23 (2) ◽  
pp. 692
Author(s):  
Mateusz Dawidziuk ◽  
Anna Kutkowska-Kazmierczak ◽  
Ewelina Bukowska-Olech ◽  
Marta Jurek ◽  
Ewa Kalka ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Sensorineural Deafness ◽  
Functional Differentiation ◽  
Actin Gene ◽  
Sequence Analyses ◽  
Present Argument ◽  
And Function ◽  
Developmental Traits ◽  
Exome Sequence

Actin molecules are fundamental for embryonic structural and functional differentiation; γ-actin is specifically required for the maintenance and function of cytoskeletal structures in the ear, resulting in hearing. Baraitser–Winter Syndrome (B-WS, OMIM #243310, #614583) is a rare, multiple-anomaly genetic disorder caused by mutations in either cytoplasmically expressed actin gene, ACTB (β-actin) or ACTG1 (γ-actin). The resulting actinopathies cause characteristic cerebrofrontofacial and developmental traits, including progressive sensorineural deafness. Both ACTG1-related non-syndromic A20/A26 deafness and B-WS diagnoses are characterized by hypervariable penetrance in phenotype. Here, we identify a 28th patient worldwide carrying a mutated γ-actin ACTG1 allele, with mildly manifested cerebrofrontofacial B-WS traits, hypervariable penetrance of developmental traits and sensorineural hearing loss. This patient also displays brachycephaly and a complete absence of speech faculty, previously unreported for ACTG1-related B-WS or DFNA20/26 deafness, representing phenotypic expansion. The patient’s exome sequence analyses (ES) confirms a de novo ACTG1 variant previously unlinked to the pathology. Additional microarray analysis uncover no further mutational basis for dual molecular diagnosis in our patient. We conclude that γ-actin c.542C > T, p.Ala181Val is a dominant pathogenic variant, associated with mildly manifested facial and cerebral traits typical of B-WS, hypervariable penetrance of developmental traits and sensorineural deafness. We further posit and present argument and evidence suggesting ACTG1-related non-syndromic DFNA20/A26 deafness is a manifestation of undiagnosed ACTG1-related B-WS.

scholarly journals Kabuki Syndrome: Identification of Two Novel Variants in KMT2Dand KDM6A

2021 ◽  
pp. 1-9
Author(s):  
Mehrnoosh Khodaeian ◽  
Ehsan Jafarinia ◽  
Fatemeh Bitarafan ◽  
Shohreh Shafeii ◽  
Navid Almadani ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Kabuki Syndrome ◽  
Functional Studies ◽  
Large Deletions ◽  
Whole Exome ◽  
Functionally Impaired ◽  
And Function

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

scholarly journals riboCIRC: a comprehensive database of translatable circRNAs

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Huihui Li ◽  
Mingzhe Xie ◽  
Yan Wang ◽  
Ludong Yang ◽  
Zhi Xie ◽  
...  
Keyword(s):  
De Novo ◽  
Species Conservation ◽  
Structure And Function ◽  
Research Community ◽  
Genome Browser ◽  
Valuable Resource ◽  
Sequence Structure ◽  
A Genome ◽  
Context Specific ◽  
And Function

AbstractriboCIRC is a translatome data-oriented circRNA database specifically designed for hosting, exploring, analyzing, and visualizing translatable circRNAs from multi-species. The database provides a comprehensive repository of computationally predicted ribosome-associated circRNAs; a manually curated collection of experimentally verified translated circRNAs; an evaluation of cross-species conservation of translatable circRNAs; a systematic de novo annotation of putative circRNA-encoded peptides, including sequence, structure, and function; and a genome browser to visualize the context-specific occupant footprints of circRNAs. It represents a valuable resource for the circRNA research community and is publicly available at http://www.ribocirc.com.

scholarly journals Pyrobaculum yellowstonensis Strain WP30 Respires on Elemental Sulfur and/or Arsenate in Circumneutral Sulfidic Geothermal Sediments of Yellowstone National Park

2015 ◽  
Vol 81 (17) ◽  
pp. 5907-5916 ◽  
Author(s):  
Z. J. Jay ◽  
J. P. Beam ◽  
A. Dohnalkova ◽  
R. Lohmayer ◽  
B. Bodle ◽  
...  
Keyword(s):  
Yellowstone National Park ◽  
National Park ◽  
Elemental Sulfur ◽  
De Novo ◽  
Hot Spring ◽  
Content Type ◽  
Physiological Attributes ◽  
And Function ◽  
Metagenome Sequence

ABSTRACTThermoproteales(phylumCrenarchaeota) populations are abundant in high-temperature (>70°C) environments of Yellowstone National Park (YNP) and are important in mediating the biogeochemical cycles of sulfur, arsenic, and carbon. The objectives of this study were to determine the specific physiological attributes of the isolatePyrobaculum yellowstonensisstrain WP30, which was obtained from an elemental sulfur sediment (Joseph's Coat Hot Spring [JCHS], 80°C, pH 6.1, 135 μM As) and relate this organism to geochemical processes occurringin situ. Strain WP30 is a chemoorganoheterotroph and requires elemental sulfur and/or arsenate as an electron acceptor. Growth in the presence of elemental sulfur and arsenate resulted in the formation of thioarsenates and polysulfides. The complete genome of this organism was sequenced (1.99 Mb, 58% G+C content), revealing numerous metabolic pathways for the degradation of carbohydrates, amino acids, and lipids. Multiple dimethyl sulfoxide-molybdopterin (DMSO-MPT) oxidoreductase genes, which are implicated in the reduction of sulfur and arsenic, were identified. Pathways for thede novosynthesis of nearly all required cofactors and metabolites were identified. The comparative genomics ofP. yellowstonensisand the assembled metagenome sequence from JCHS showed that this organism is highly related (∼95% average nucleotide sequence identity) toin situpopulations. The physiological attributes and metabolic capabilities ofP. yellowstonensisprovide an important foundation for developing an understanding of the distribution and function of these populations in YNP.

scholarly journals Steroidogenic Factor-1 (SF-1)-Driven Differentiation of Murine Embryonic Stem (ES) Cells into a Gonadal Lineage

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2870-2882 ◽  
Author(s):  
Unmesh Jadhav ◽  
J. Larry Jameson
Keyword(s):  
Target Genes ◽  
De Novo ◽  
Embryoid Body ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Culture Conditions ◽  
Steroidogenic Factor 1 ◽  
Lineage Differentiation ◽  
And Function

Steroidogenic factor 1 (SF-1) is essential for the development and function of steroidogenic tissues. Stable incorporation of SF-1 into embryonic stem cells (SF-1-ES cells) has been shown to prime the cells for steroidogenesis. When provided with exogenous cholesterol substrate, and after treatment with retinoic acid and cAMP, SF-1-ES cells produce progesterone but do not produce other steroids such as cortisol, estradiol, or testosterone. In this study, we explored culture conditions that optimize SF-1-mediated differentiation of ES cells into defined steroidogenic lineages. When embryoid body formation was used to facilitate cell lineage differentiation, SF-1-ES cells were found to be restricted in their differentiation, with fewer cells entering neuronal pathways and a larger fraction entering the steroidogenic lineage. Among the differentiation protocols tested, leukemia inhibitory factor (LIF) removal, followed by prolonged cAMP treatment was most efficacious for inducing steroidogenesis in SF-1-ES cells. In this protocol, a subset of SF-1-ES cells survives after LIF withdrawal, undergoes morphologic differentiation, and recovers proliferative capacity. These cells are characterized by induction of steroidogenic enzyme genes, use of de novo cholesterol, and production of multiple steroids including estradiol and testosterone. Microarray studies identified additional pathways associated with SF-1 mediated differentiation. Using biotinylated SF-1 in chromatin immunoprecipitation assays, SF-1 was shown to bind directly to multiple target genes, with induction of binding to some targets after steroidogenic treatment. These studies indicate that SF-1 expression, followed by LIF removal and treatment with cAMP drives ES cells into a steroidogenic pathway characteristic of gonadal steroid-producing cells.

scholarly journals A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal

2017 ◽  
Vol 28 (22) ◽  
pp. 3095-3111 ◽  
Author(s):  
Courtney A. Copeland ◽  
Bing Han ◽  
Ajit Tiwari ◽  
Eric D. Austin ◽  
James E. Loyd ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
De Novo ◽  
Dominant Negative ◽  
Caveolin 1 ◽  
Protein Levels ◽  
C Terminus ◽  
Er Retention ◽  
And Function ◽  
Er Retention Signal ◽  
Retention Signal

Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in numerous physiological processes. Recent studies have identified heterozygous mutations in the CAV1 gene in patients with pulmonary arterial hypertension (PAH), but the mechanisms by which these mutations impact caveolae assembly and contribute to disease remain unclear. To address this question, we examined the consequences of a familial PAH-associated frameshift mutation in CAV1, P158PfsX22, on caveolae assembly and function. We show that C-terminus of the CAV1 P158 protein contains a functional ER-retention signal that inhibits ER exit and caveolae formation and accelerates CAV1 turnover in Cav1–/– MEFs. Moreover, when coexpressed with wild-type (WT) CAV1 in Cav1–/– MEFs, CAV1-P158 functions as a dominant negative by partially disrupting WT CAV1 trafficking. In patient skin fibroblasts, CAV1 and caveolar accessory protein levels are reduced, fewer caveolae are observed, and CAV1 complexes exhibit biochemical abnormalities. Patient fibroblasts also exhibit decreased resistance to a hypo-osmotic challenge, suggesting the function of caveolae as membrane reservoir is compromised. We conclude that the P158PfsX22 frameshift introduces a gain of function that gives rise to a dominant negative form of CAV1, defining a new mechanism by which disease-associated mutations in CAV1 impair caveolae assembly.

Abstract 17081: End Stage Mitochondrial Cardiomyopathy And Heart Transplantation Due To Pathogenic Biallelic C1QBP Variants

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Nicholas S Wilcox ◽  
Stuart Prenner ◽  
Marisa Cevasco ◽  
Courtney Condit ◽  
Amy Goldstein ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Heart Transplantation ◽  
Genome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Late Onset ◽  
Genetic Disorder ◽  
Disease Onset ◽  
Serum Lactate ◽  
Metabolic Decompensation

Case Presentation: A 29-year-old male with LVH diagnosed in childhood was admitted with acute HF. TTE showed LVEF 5-10% and LV thrombi for which he was anticoagulated. He received inappropriate ICD shocks due to T wave oversensing, leading to cardiogenic shock requiring VA-ECMO support. Serum lactate peaked at 17 mmol/L due to cardiac and metabolic decompensation. He underwent heart transplantation (HT) on hospital day (HD) 8 and tolerated standard immunosuppression. First endomyocardial biopsy showed acute cellular rejection requiring pulse steroids. He was discharged on HD 33. Trio whole exome and mitochondrial genome sequencing revealed biallelic variants in complement component 1Q subcomponent-binding protein ( C1QBP ), due to a maternally inherited likely pathogenic variant c.612C>G (p.F204L in exon 5) and an apparently de novo deletion of 17p13.2, spanning exons 4-6 of C1QBP and exon 6 of the RPAIN gene. Mitochondrial genome sequencing of the explanted heart revealed multiple large-scale mitochondrial DNA deletions at 33% heteroplasmy. Discussion: C1QBP variants are associated with mitochondrial and multi-organ dysfunction. Only 12 patients exhibiting biallelic C1QBP variants are reported. Four died in the peripartum period due to fetal hydrops or HF; 5 exhibited early-onset cardiomyopathy (CM); 3 others had late-onset ophthalmoplegia without CM. The p.F204L variant has been reported in 1 patient with compound C1QBP p.F204L/p.C186S heterozygosity who died from hydrops fetalis and a second with p.F204L homozygosity with late-onset ophthalmoplegia and skeletal myopathy without CM. Differences in the size, heteroplasmy, and tissue distribution of mitochondrial genome secondary deletions may explain variability in disease onset and progression. We present the first patient with biallelic pathogenic C1QBP gene variants with mitochondrial CM to undergo HT and highlight the diagnosis and management of an exceptionally uncommon genetic disorder.

scholarly journals T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Kiekens ◽  
Wouter Van Loocke ◽  
Sylvie Taveirne ◽  
Sigrid Wahlen ◽  
Eva Persyn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Current Knowledge ◽  
Functional Differentiation ◽  
Cell Maturation ◽  
Hematopoietic Stem ◽  
And Function

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.

scholarly journals A de novo approach to disentangle partner identity and function in holobiont systems

2017 ◽  
Author(s):  
Arnaud Meng ◽  
Camille Marchet ◽  
Erwan Corre ◽  
Pierre Peterlongo ◽  
Adriana Alberti ◽  
...  
Keyword(s):  
Functional Diversity ◽  
De Novo ◽  
Model Organisms ◽  
Symbiotic Association ◽  
Proof Of Concept ◽  
Short Read ◽  
Symbiotic Associations ◽  
Functional Annotations ◽  
And Function ◽  
Similarity Method

AbstractBackgroundStudy of meta-transcriptomic datasets involving non-model organisms represents bioinformatic challenges. The production of chimeric sequences and our inability to distinguish the taxonomic origins of the sequences produced are inherent and recurrent difficulties in de novo assembly analyses. The study of holobiont transcriptomes shares similarities with meta-transcriptomic, and hence, is also affected by challenges invoked above. Here we propose an innovative approach to tackle such difficulties which was applied to the study of marine holobiont models as a proof of concept.ResultsWe considered three holobionts models, of which two transcriptomes were previously assembled and published, and a yet unpublished transcriptome, to analyze their raw reads and assign them to the host and/or to the symbiont(s) using Short Read Connector, a k-mer based similarity method. We were able to define four distinct categories of reads for each holobiont transcriptome: host reads, symbiont reads, shared reads and unassigned reads. The result of the independent assemblies for each category within a transcriptome led to a significant diminution of de novo assembled chimeras compared to classical assembly methods. Combining independent functional and taxonomic annotations of each partner’s transcriptome is particularly convenient to explore the functional diversity of an holobiont. Finally, our strategy allowed to propose new functional annotations for two well-studied holobionts and a first transcriptome from a planktonic Radiolaria-Dinophyta system forming widespread symbiotic association for which our knowledge is limited. ConclusionsIn contrast to classical assembly approaches, our bioinformatic strategy not only allows biologists to studying separately host and symbiont data from a holobiont mixture, but also generates improved transcriptome assemblies. The use of Short Read Connector has proven to be an effective way to tackle meta-transcriptomic challenges to study holobiont systems composed of either well-studied or poorly characterized symbiotic lineages such as the newly sequenced marine plankton Radiolaria-Dinophyta symbiosis and ultimately expand our knowledge about these marine symbiotic associations.

scholarly journals Identification and Functional Characterization of a Novel De Novo RUNX2 Frameshift Mutation Associated With Cleidocranial Dysplasia

2021 ◽  
Author(s):  
Lei Gong ◽  
Bekzod Odilov ◽  
Feng Han ◽  
Fuqiang Liu ◽  
Yujing Sun ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
De Novo ◽  
Novel Mutation ◽  
Genetic Disorder ◽  
Functional Characterization ◽  
Sporadic Case ◽  
Luciferase Assay ◽  
Cleidocranial Dysplasia ◽  
Wild Type ◽  
Bone And Cartilage Development

Abstract BackgroundCleidocranial dysplasia (CCD) is a rare genetic disorder affecting bone and cartilage development. Clinical features of CCD comprise short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles and multiple dental anomalies. Several studies have revealed that CCD development is strongly linked with different mutations in Runt-related Transcription Factor 2 (RUNX2) gene. In this study, we report a case with typical CCD presentations. MethodsWe performed genetic testing of participants and found a novel RUNX2 frameshift mutation: c.1550delT in a sporadic case. We also compared the functional activity of the mutant and wild-type RUNX2 through immunofluorescence microscopy and osteocalcin promoter luciferase assay. ResultsBoth mutant RUNX2 and wild‑type RUNX2 protein were similarly confined in the nuclei. The novel mutation caused abrogative transactivation activity of RUNX2 on osteocalcin promoter. ConclusionsWe explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding emphasizes on crucial role of VWRPY domain in RUNX2 transactivation ability.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

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