Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.603
Filtrar
1.
Int J Mol Sci ; 25(7)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38612864

RESUMO

Flavonoids exhibit various bioactivities including anti-oxidant, anti-tumor, anti-inflammatory, and anti-viral properties. Methylated flavonoids are particularly significant due to their enhanced oral bioavailability, improved intestinal absorption, and greater stability. The heterologous production of plant flavonoids in bacterial factories involves the need for enough biosynthetic precursors to allow for high production levels. These biosynthetic precursors are malonyl-CoA and l-tyrosine. In this work, to enhance flavonoid biosynthesis in Streptomyces albidoflavus, we conducted a transcriptomics study for the identification of candidate genes involved in l-tyrosine catabolism. The hypothesis was that the bacterial metabolic machinery would detect an excess of this amino acid if supplemented with the conventional culture medium and would activate the genes involved in its catabolism towards energy production. Then, by inactivating those overexpressed genes (under an excess of l-tyrosine), it would be possible to increase the intracellular pools of this precursor amino acid and eventually the final flavonoid titers in this bacterial factory. The RNAseq data analysis in the S. albidoflavus wild-type strain highlighted the hppD gene encoding 4-hydroxyphenylpyruvate dioxygenase as a promising target for knock-out, exhibiting a 23.2-fold change (FC) in expression upon l-tyrosine supplementation in comparison to control cultivation conditions. The subsequent knock-out of the hppD gene in S. albidoflavus resulted in a 1.66-fold increase in the naringenin titer, indicating enhanced flavonoid biosynthesis. Leveraging the improved strain of S. albidoflavus, we successfully synthesized the methylated flavanones hesperetin, homoeriodictyol, and homohesperetin, achieving titers of 2.52 mg/L, 1.34 mg/L, and 0.43 mg/L, respectively. In addition, the dimethoxy flavanone homohesperetin was produced as a byproduct of the endogenous metabolism of S. albidoflavus. To our knowledge, this is the first time that hppD deletion was utilized as a strategy to augment the biosynthesis of flavonoids. Furthermore, this is the first report where hesperetin and homoeriodictyol have been synthesized from l-tyrosine as a precursor. Therefore, transcriptomics is, in this case, a successful approach for the identification of catabolism reactions affecting key precursors during flavonoid biosynthesis, allowing the generation of enhanced production strains.


Assuntos
Anormalidades Craniofaciais , Flavonas , Flavonoides , Perfilação da Expressão Gênica , Hesperidina , Streptomyces , Aminoácidos , Tirosina
2.
J Clin Invest ; 134(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557491

RESUMO

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.


Assuntos
Anormalidades Múltiplas , Acetilcarnitina , Hipotireoidismo Congênito , Anormalidades Craniofaciais , Histona Acetiltransferases , Deficiência Intelectual , Instabilidade Articular , Animais , Humanos , Camundongos , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/genética , Acetilação , Acetilcarnitina/farmacologia , Acetilcarnitina/uso terapêutico , Blefarofimose , Cromatina , Anormalidades Craniofaciais/tratamento farmacológico , Anormalidades Craniofaciais/genética , Éxons , Facies , Cardiopatias Congênitas , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Histonas/genética , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética
3.
BMC Genomics ; 25(1): 374, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627644

RESUMO

BACKGROUND: Fatty liver hemorrhagic syndrome (FLHS) in the modern poultry industry is primarily caused by nutrition. Despite encouraging progress on FLHS, the mechanism through which nutrition influences susceptibility to FLHS is still lacking in terms of epigenetics. RESULTS: In this study, we analyzed the genome-wide patterns of trimethylated lysine residue 27 of histone H3 (H3K27me3) enrichment by chromatin immunoprecipitation-sequencing (ChIP-seq), and examined its association with transcriptomes in healthy and FLHS hens. The study results indicated that H3K27me3 levels were increased in the FLHS hens on a genome-wide scale. Additionally, H3K27me3 was found to occupy the entire gene and the distant intergenic region, which may function as silencer-like regulatory elements. The analysis of transcription factor (TF) motifs in hypermethylated peaks has demonstrated that 23 TFs are involved in the regulation of liver metabolism and development. Transcriptomic analysis indicated that differentially expressed genes (DEGs) were enriched in fatty acid metabolism, amino acid, and carbohydrate metabolism. The hub gene identified from PPI network is fatty acid synthase (FASN). Combined ChIP-seq and transcriptome analysis revealed that the increased H3K27me3 and down-regulated genes have significant enrichment in the ECM-receptor interaction, tight junction, cell adhesion molecules, adherens junction, and TGF-beta signaling pathways. CONCLUSIONS: Overall, the trimethylation modification of H3K27 has been shown to have significant regulatory function in FLHS, mediating the expression of crucial genes associated with the ECM-receptor interaction pathway. This highlights the epigenetic mechanisms of H3K27me3 and provides insights into exploring core regulatory targets and nutritional regulation strategies in FLHS.


Assuntos
Anormalidades Múltiplas , Anormalidades Craniofaciais , Dieta com Restrição de Proteínas , Fígado Gorduroso , Transtornos do Crescimento , Comunicação Interventricular , Animais , Feminino , Histonas/metabolismo , Galinhas/genética , Galinhas/metabolismo , Epigênese Genética , Fígado Gorduroso/genética , Fígado Gorduroso/veterinária , Hemorragia/genética , Transcriptoma
5.
Med J Malaysia ; 79(Suppl 1): 168-175, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38555902

RESUMO

INTRODUCTION: Lower Cross Syndrome (LCS) is a prevalent condition that manifests as muscular tension due to the asymmetry in the strength of the lower extremity muscles. This imbalance could be due to the tautness of the iliopsoas, rectus femoris, tensor fascia latae, adductor group, gastrocnemius, and soleus muscles. LCS causes a postural imbalance in the individual, which triggers low back pain (LBP). When LCS is present alongside LBP, may cause the upper body to sway more in the transverse plane and at the lumbar level, making walking and termination of gait (GT) more difficult. However, the evidence of motor control and gait performance is scarce with inconclusive findings. Thus, this study aimed to review motor control on gait performance among individuals with lower crossed syndrome. This review is conducted to determine the motor control on gait performance in patients with LCS and how the conditions affect gait. MATERIALS AND METHODS: The databases Google Scholar, Science Direct, ResearchGate, PubMed, and Scopus were searched to identify potentially relevant documents. The keywords used for the search included "motor control" OR "motor learning" OR" core stability" AND "lower crossed syndrome" AND "gait". The search includes articles published between 1970 and 2022 and written in English. It is excluded when the paper is not a full-text article. After finding the articles, the information was extracted, including author, year of publication, country, objective, type of study, and motor control analysis summary. RESULTS: There were 107 articles retrieved from the search. but only seventeen articles were included for analysis. The finding demonstrates that LCS may associate with LBP and reduces the motor control of the core muscle stability which indirectly influences gait performance. CONCLUSIONS: This study suggests that individuals with LCS will have an alteration in their gait. However, there is still insufficient information on motor control in gait performance among lower crossed syndrome. Further research is needed to find what factors that may contribute to the adaptation of motor control in gait among LCS population.


Assuntos
Anormalidades Múltiplas , Anormalidades Craniofaciais , Dor Lombar , Transtornos da Pigmentação , Humanos , Marcha/fisiologia , Músculo Esquelético
6.
Taiwan J Obstet Gynecol ; 63(2): 238-241, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38485322

RESUMO

OBJECTIVE: Kleefstra syndrome (KS), formerly known as 9q subtelomeric deletion syndrome, is characterized by multiple structural abnormalities. However, most fetuses do not have obvious abnormal phenotypes. In this study, the fetus with KS presented with multiple system structural anomalies, and we aimed to explore the genotype-phenotype correlations of KS fetuses. CASE REPORT: Multiple systematic structural anomalies, including severe intrauterine growth restriction (IUGR) and cardiac defects, were detected by ultrasound in the fetus at 33 + 5 weeks' gestation. These abnormalities may be caused by the pathogenic deleted fragment at 9q34.3, including the euchromatic histone methyltransferase 1 (EHMT1) and collagen type V alpha 1 chain (COL5A1) genes, detected by copy number variation sequencing (CNV-seq). CONCLUSIONS: It is essential for clinicians to perform CNV-seq combined with multidisciplinary consultation for suspected KS fetuses, especially those with multiple systematic structural anomalies.


Assuntos
Anormalidades Múltiplas , Anormalidades Craniofaciais , Cardiopatias Congênitas , Deficiência Intelectual , Humanos , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/genética , Deleção Cromossômica , Deficiência Intelectual/genética , Anormalidades Múltiplas/genética , Feto/patologia , Estudos de Associação Genética , Cromossomos Humanos Par 9/genética
7.
Mol Genet Genomic Med ; 12(3): e2411, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38433559

RESUMO

BACKGROUND: Hemifacial macrosomia (HFM, OMIM 164210) is a complex and highly heterogeneous disease. FORKHEAD BOX I3 (FOXI3) is a susceptibility gene for HFM, and mice with loss of function of Foxi3 did exhibit a phenotype similar to craniofacial dysmorphism. However, the specific pathogenesis of HFM caused by FOXI3 deficiency remains unclear till now. METHOD: In this study, we first constructed a Foxi3 deficiency (Foxi3-/- ) mouse model to verify the craniofacial phenotype of Foxi3-/- mice, and then used RNAseq data for gene differential expression analysis to screen candidate pathogenic genes, and conducted gene expression verification analysis using quantitative real-time PCR. RESULTS: By observing the phenotype of Foxi3-/- mice, we found that craniofacial dysmorphism was present. The results of comprehensive bioinformatics analysis suggested that the craniofacial dysmorphism caused by Foxi3 deficiency may be involved in the PI3K-Akt signaling pathway. Quantitative real-time PCR results showed that the expression of PI3K-Akt signaling pathway-related gene Akt2 was significantly increased in Foxi3-/- mice. CONCLUSION: The craniofacial dysmorphism caused by the deficiency of Foxi3 may be related to the expression of Akt2 and PI3K-Akt signaling pathway. This study laid a foundation for understanding the function of FOXI3 and the pathogenesis and treatment of related craniofacial dysmorphism caused by FOXI3 dysfunction.


Assuntos
Anormalidades Craniofaciais , Anormalidades Musculoesqueléticas , Animais , Camundongos , Biologia Computacional , Anormalidades Craniofaciais/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/genética
8.
J Zoo Wildl Med ; 55(1): 277-284, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38453512

RESUMO

Two female (FL 1, FL 2) and one male (ML) 11-wk-old, intact, captive African lion cubs (Panthera leo leo) were presented with a history of mild vestibular signs. Initial serum vitamin A concentrations were low (140 nmol/L) for ML. Calvarial hyperostosis was confirmed using computed tomography (CT) of the head and cervical vertebrae in each cub. CT measurements were adapted in relation to the skull width. ML showed the most pronounced thickening of the tentorium cerebelli and occipital bone, represented by a tentorium cerebelli to skull width ratio (TCR) of 0.08 (FL 1: 0.06, FL 2: 0.05) and a basisphenoid to skull width ratio (BBR) of 0.07 (FL 1: 0.06, FL 2: 0.04). Magnetic resonance imaging (MRI) revealed cerebellar herniation and cervical intramedullary T2-weighted hyperintensity from C1, extending caudally for at least two cervical vertebrae in all cubs. Treatment was initiated with subcutaneous vitamin A supplementation and feeding of whole carcasses. Improvement in ataxia was noticed 3 wk later. Follow-up CT and MRI examinations were performed in ML after 3 and 8 mon. The affected bones appeared slightly less thickened and TCR and BBR had decreased to 0.05 after 3 mon. The cerebellum remained mildly herniated, accompanied by amelioration of cervical T2w hyperintensities. After 8 mon, evaluation and diagnostic imaging revealed further improvement regarding the neurologic status and measurements (TCR 0.05, BBR 0.04) despite persistence of a subtle cerebellar herniation. In conclusion, bone remodeling and improvement in clinical signs may be achievable in young lion cubs presented with calvarial hyperostosis and may be attributable to high-dose vitamin A supplementation.


Assuntos
Anormalidades Craniofaciais , Hiperostose , Leões , Deficiência de Vitamina A , Masculino , Feminino , Animais , Vitamina A/uso terapêutico , Deficiência de Vitamina A/veterinária , Encefalocele/complicações , Encefalocele/tratamento farmacológico , Encefalocele/veterinária , Suplementos Nutricionais , Receptores de Antígenos de Linfócitos T
10.
Poult Sci ; 103(4): 103482, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387286

RESUMO

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disorder observed in egg-laying hens, characterized by fatty deposits and cellular steatosis in the liver. Our preliminary investigations have revealed a marked decrease in the concentration of butyric acid in the FLHS strain of laying hens. It has been established that sodium butyrate (NaB) protects against metabolic disorders. However, the underlying mechanism by which butyrate modulates hepato-lipid metabolism to a great extent remains unexplored. In this study, we constructed an isolated in vitro model of chicken primary hepatocytes to induce hepatic steatosis by free fatty acids (FFA). Our results demonstrate that treatment with NaB effectively mitigated FFA-induced hepatic steatosis in chicken hepatocytes by inhibiting lipid accumulation, downregulating the mRNA expression of lipo-synthesis-related genes (sterol regulatory element binding transcription factor 1 (SREBF1), acetyl-CoA carboxylase 1(ACC1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), liver X receptor α (LXRα), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)) (P < 0.05), and upregulating the mRNA and protein expression of AMP-activated protein kinase α1 (AMPKα1), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyl-transferase 1A (CPT1A) (P < 0.05). Moreover, AMPK and PPARα inhibitors (Compound C (Comp C) and GW6471, respectively) reversed the protective effects of NaB against FFA-induced hepatic steatosis by blocking the AMPK/PPARα pathway, leading to lipid droplet accumulation and triglyceride (TG) contents in chicken primary hepatocytes. With these findings, NaB can alleviate hepatocyte lipoatrophy injury by activating the AMPK/PPARα pathway, promoting fatty acid oxidation, and reducing lipid synthesis in chicken hepatocytes, potentially being able to provide new ideas for the treatment of FLHS.


Assuntos
Anormalidades Múltiplas , Anormalidades Craniofaciais , Fígado Gorduroso , Transtornos do Crescimento , Comunicação Interventricular , PPAR alfa , Animais , Feminino , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR alfa/farmacologia , Galinhas/genética , Ácidos Graxos não Esterificados/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Butírico/farmacologia , Ácido Butírico/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/veterinária , Fígado/metabolismo , Hepatócitos , Metabolismo dos Lipídeos , RNA Mensageiro/metabolismo , Ácidos Graxos/metabolismo
11.
Hum Cell ; 37(3): 832-839, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38372889

RESUMO

Pathogenic variants of the KCNH1 gene can cause dominant-inherited Temple-Baraitser/Zimmermann-Laband syndrome with severe mental retardation, seizure, gingival hyperplasia and nail hypoplasia. This study established an induced pluripotent stem cell (iPSC) line using urinary cells from a girl with KCNH1 recurrent/hotspot pathogenic variant c.1070G > A (p.R357Q). The cell identity, pluripotency, karyotypic integrity, absence of reprogramming virus and mycoplasma contamination, and differential potential to three germ layers of the iPSC line, named as ZJUCHi003, were characterized and confirmed. Furthermore, ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons. This cell line will be useful for investigating the pathogenic mechanisms of KCNH1 variants-associated symptoms, as well as for evaluating novel therapeutic approaches.


Assuntos
Anormalidades Múltiplas , Anormalidades Craniofaciais , Fibromatose Gengival , Hallux/anormalidades , Deformidades Congênitas da Mão , Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual , Unhas Malformadas , Polegar/anormalidades , Feminino , Humanos , Deficiência Intelectual/genética , Anormalidades Múltiplas/genética , Mutação , Canais de Potássio Éter-A-Go-Go/genética
12.
Eur J Med Genet ; 68: 104924, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38355094

RESUMO

Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the BMPER gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel BMPER mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.


Assuntos
Anormalidades Craniofaciais , Disostoses , Osteocondrodisplasias , Costelas/anormalidades , Escoliose , Coluna Vertebral/anormalidades , Feminino , Humanos , Adolescente , Escoliose/diagnóstico por imagem , Escoliose/genética , Coluna Vertebral/diagnóstico por imagem , Disostoses/diagnóstico por imagem , Disostoses/genética , Costelas/diagnóstico por imagem , Proteínas de Transporte
13.
J Hum Genet ; 69(3-4): 139-144, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38321215

RESUMO

BACKGROUND: Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in ZFP36L2 and its functional relevance in zebrafish models. METHODS: We analyzed genetic data of the Chinese Han population from two previous GWAS, comprising of 2512 cases and 2255 controls. Based on the Hardy-Weinberg Equilibrium (HWE) and minor allele frequency (MAF), SNPs in the ZFP36L2 were selected for association analysis. In addition, zebrafish models were used to clarify the in-situ expression pattern of zfp36l2 and the impact of its Morpholino-induced knockdown. RESULTS: Via association analysis, rs7933 in ZFP36L2 was significantly associated with various non-syndromic cleft lip-only subtypes, potentially conferring a protective effect. Zebrafish embryos showed elevated expression of zfp36l2 in the craniofacial region during critical stages of oral cavity formation. Furthermore, Morpholino-induced knockdown of zfp36l2 led to craniofacial abnormalities, including cleft lip, which was partially rescued by the addition of zfp36l2 mRNA. CONCLUSION: Our findings highlight the significance of ZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations.


Assuntos
Fenda Labial , Fissura Palatina , Anormalidades Craniofaciais , Animais , Humanos , Fenda Labial/genética , Fissura Palatina/genética , Peixe-Zebra , Predisposição Genética para Doença , Morfolinos , Polimorfismo de Nucleotídeo Único , Genótipo , Fatores de Transcrição/genética
14.
Artigo em Chinês | MEDLINE | ID: mdl-38297854

RESUMO

Objective:To investigate the management of granulation tissue during surgery for infected congenital preauricular fistula and to assess the surgical outcomes. Methods:To summarize the surgical methods and the treatment of granulation methods in 140 cases of congenital preauricular fistula during the period of infection treated in our department from January 2018 to September 2022. The study divided patients into an observation group (79 patients) undergoing fistulectomy without granulation treatment, and a control group (61 patients) where fistulectomy and granulation resection were performed concurrently.. After six months of follow-up, the wound healing, recurrence rates, and the aesthetic assessment of granulation healing were evaluated using the Stony Brook Scar Evaluation Scale(SBSES). Results:The two surgical approaches were applied to a total of 140 patients with infected congenital preauricular fistula. There was no statistical difference in wound healing and recurrence rates between the observation group and the control group. However, the observation group exhibited smaller scars. Conclusion:In cases of infected congenital preauricular fistula, surgical removal without excising granulation tissue is feasible, leading to effective healing and lesser scar formation.


Assuntos
Anormalidades Craniofaciais , Fístula , Humanos , Cicatriz , Cicatrização , Fístula/cirurgia , Resultado do Tratamento
15.
J AAPOS ; 28(2): 103833, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38360349

RESUMO

Improving access to comfortable and well-fitting glasses for children with craniofacial differences may improve their visual outcomes. The purpose of this study was to describe challenges in spectacle fitting facing patients with frontonasal dysplasia and to report successful methods for creating custom 3D designed glasses. Additionally, the process of systematically collecting and analyzing spectacle-fitting challenges can inform future processes of automated design of 3D printed glasses and can be applied to other specific craniofacial syndromes.


Assuntos
Anormalidades Craniofaciais , Óculos , Criança , Humanos , Face , Anormalidades Craniofaciais/terapia
16.
PLoS One ; 19(1): e0296328, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38165902

RESUMO

The SET binding protein 1 (SETBP1) gene encodes a transcription factor (TF) involved in various cellular processes. Variants in SETBP1 can result in three different diseases determined by the introduction (germline vs. somatic) and location of the variant. Germline variants cause the ultra-rare pediatric Schinzel Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disorder (SETBP1-HD), characterized by severe multisystemic abnormalities with neurodegeneration or a less severe brain phenotype accompanied by hypotonia and strabismus, respectively. Somatic variants in SETBP1 are associated with hematological malignancies and cancer development in other tissues in adults. To better understand the tissue-specific mechanisms involving SETBP1, we analyzed publicly available RNA-sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project. We found SETBP1 and its known target genes were widely expressed across 31 adult human tissues. K-means clustering identified three distinct expression patterns of SETBP1 targets across tissues. Functional enrichment analysis (FEA) of each cluster revealed gene sets related to transcriptional regulation, DNA binding, and mitochondrial function. TF activity analysis of SETBP1 and its target TFs revealed tissue-specific TF activity, underscoring the role of tissue context-driven regulation and suggesting its impact in SETBP1-associated disease. In addition to uncovering tissue-specific molecular signatures of SETBP1 expression and TF activity, we provide a Shiny web application to facilitate exploring TF activity across human tissues for 758 TFs. This study provides insight into the landscape of SETBP1 expression and TF activity across 31 non-diseased human tissues and reveals tissue-specific expression and activity of SETBP1 and its targets. In conjunction with the web application we constructed, our framework enables researchers to generate hypotheses related to the role tissue backgrounds play with respect to gene expression and TF activity in different disease contexts.


Assuntos
Proteínas de Transporte , Proteínas Nucleares , Humanos , Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Anormalidades Craniofaciais/genética , Expressão Gênica , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Am J Med Genet A ; 194(5): e63516, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38168088

RESUMO

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades Craniofaciais , Deficiência Intelectual , Megalencefalia , Displasia Septo-Óptica , Síndrome de Sotos , Criança , Humanos , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Éxons/genética , Megalencefalia/genética , Deficiência Intelectual/genética , Análise de Sequência de RNA
19.
Clin Genet ; 105(5): 499-509, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38221796

RESUMO

Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades Craniofaciais , Surdez , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Peptidase 7 Específica de Ubiquitina/genética , Deficiência Intelectual/genética , Deficiência Intelectual/complicações , Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo
20.
Prenat Diagn ; 44(3): 369-372, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38163266

RESUMO

Raine syndrome (MIM 259775) is a rare autosomal recessive disorder, first described by Raine et al. in 1989, with an estimated prevalence of <1/1,000,000. This is due to pathogenic variants in FAM20C characterized by osteosclerosis, typical craniofacial features, and brain calcifications. Here, we report a novel variant in FAM20C, describe a uniquely severe craniofacial and CNS phenotype of Raine syndrome, and correlate it with prenatal findings. Fetal phenotyping was based on ultrasound and MRI. Solo exome sequencing was performed from DNA extracted from postmortem skin biopsy. Targeted parental variant testing was subsequently performed. A homozygous missense variant NM_020223.4 (c.1445 G > A (p.Gly482Glu)) was identified in FAM20C associated with Raine syndrome. The infant had the characteristic dysmorphic features seen in Raine syndrome. He had particularly significant CNS manifestations consisting of multisuture craniosynostosis with protrusion of the brain parenchyma through fontanelles and cranial lacunae. Histological sections of the brain showed marked periventricular gliosis with regions of infarction, hemorrhage, and cavitation with global periventricular leukomalacia. Numerous dystrophic calcifications were diffusely present. Here, we demonstrate the identification of a novel variant in FAM20C in an infant with the characteristic features seen in Raine syndrome. The patient expands the characteristic phenotype of Raine syndrome to include a uniquely severe CNS phenotype, first identified on prenatal imaging.


Assuntos
Anormalidades Múltiplas , Encefalopatias , Fissura Palatina , Anormalidades Craniofaciais , Exoftalmia , Microcefalia , Osteosclerose , Sinostose , Masculino , Lactente , Humanos , Gravidez , Feminino , Proteínas da Matriz Extracelular/genética , Caseína Quinase I/genética , Osteosclerose/diagnóstico por imagem , Osteosclerose/genética , Encéfalo/diagnóstico por imagem , Fenótipo , Sinostose/complicações , Crânio
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...