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1.
Cells ; 13(13)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38994932

RESUMO

Chromosomal rearrangements can interfere with the disjunction and segregation of other chromosome pairs not involved in the rearrangements, promoting the occurrence of numerical abnormalities in resulting gametes and predisposition to trisomy in offspring. This phenomenon of interference is known as the interchromosomal effect (ICE). Here we report a prenatal case potentially generated by ICE. The first-trimester screening ultrasound of the pregnant woman was normal, but the NIPT indicated a high risk for three copies of chromosome 21, thus suspecting trisomy 21 (T21). After a comprehensive clinical evaluation and genetic counseling, the couple decided to undergo amniocentesis. The prenatal karyotype confirmed T21 but also showed a balanced translocation between the long arm of chromosome 15 (q22) and the long arm of chromosome 22. The parents' karyotypes also showed that the mother had the 15;22 translocation. We reviewed T21 screening methods, and we performed a literature review on ICE, a generally overlooked phenomenon. We observed that ours is the first report of a prenatal case potentially due to ICE derived from the mother. The recurrence risk of aneuploidy in the offspring of translocated individuals is likely slightly increased, but it is not possible to estimate to what extent. In addition to supporting observations, there are still open questions such as, how frequent is ICE? How much is the aneuploidy risk altered by ICE?


Assuntos
Síndrome de Down , Herança Materna , Translocação Genética , Humanos , Feminino , Translocação Genética/genética , Síndrome de Down/genética , Gravidez , Adulto , Herança Materna/genética , Feto , Cromossomos Humanos Par 15/genética
4.
Zhonghua Xue Ye Xue Za Zhi ; 45(4): 383-387, 2024 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-38951067

RESUMO

Twelve DEK-NUP214 fusion gene-positive patients with acute myeloid leukemia and on allo-HSCT treatment at the Hematology Hospital of the Chinese Academy of Medical Sciences from November 2016 to August 2022 were included in the study, and their clinical data were retrospectively analyzed. The patients comprised five men and seven women with a median age of 34 (16-52) years. At the time of diagnosis, all the patients were positive for the DEK-NUP214 fusion gene. Chromosome karyotyping analysis showed t (6;9) (p23;q34) translocation in 10 patients (two patients did not undergo chromosome karyotyping analysis), FLT3-ITD mutation was detected in 11 patients, and high expression of WT1 was observed in 11 patients. Nine patients had their primary disease in the first complete remission state before transplantation, one patient had no disease remission, and two patients were in a recurrent state. All patients received myeloablative pretreatment, five patients received sibling allogeneic hematopoietic stem cell transplantation, and seven patients received haploid hematopoietic stem cell transplantation. The median number of mononuclear cells in the transplant was 10.87 (7.09-17.89) ×10(8)/kg, and the number of CD34(+) cells was 3.29 (2.53-6.10) ×10(6)/kg. All patients achieved blood reconstruction, with a median time of 14 (10-20) days for neutrophil implantation and 15 (9-27) days for platelet implantation. The 1 year transplant-related mortality rate after transplantation was 21.2%. The cumulative recurrence rates 1 and 3 years after transplantation were 25.0% and 50.0%, respectively. The leukemia free survival rates were (65.6±14.0) % and (65.6±14.0) %, respectively. The overall survival rates were (72.2±13.8) % and (72.2±13.8) %, respectively.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Complexo de Proteínas Formadoras de Poros Nucleares , Transplante Homólogo , Humanos , Masculino , Feminino , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Adolescente , Estudos Retrospectivos , Adulto Jovem , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Oncogênicas/genética , Translocação Genética
5.
Rinsho Ketsueki ; 65(6): 492-497, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38960646

RESUMO

A 69-year-old man presented with lumbago and was diagnosed with multiple myeloma (IgD-λ type, R-ISS stage II) with bone-destructive lesions in the lumbar spine and sacrum. Chromosome analysis showed t (8;14)(q24;q32) and t (11;14)(q13;q32). Treatment with daratumumab, lenalidomide, and dexamethasone resulted in partial response, but the disease relapsed, with a copy number increase in t (11;14) and abnormal amplification of the 1q21 region. The patient was treated for CMV enteritis, and was admitted to the hospital due to sudden abdominal pain. Gastrointestinal perforation was diagnosed by CT scan showing free air and wall thickening in the small intestine. Emergency surgery was performed, and the tumors in the perforated area were positive for CCND1 but negative for MYC on immunostaining. The patient's general condition did not improve after the surgery and he died. Pathological autopsy revealed extramedullary infiltration of multiple organs in addition to the small intestine. Extramedullary infiltration is thought to be caused by clonal evolution, and further research is warranted to clarify its pathogenesis and establish effective therapeutic strategies in high-risk patients.


Assuntos
Mieloma Múltiplo , Humanos , Masculino , Mieloma Múltiplo/patologia , Mieloma Múltiplo/diagnóstico , Idoso , Evolução Fatal , Translocação Genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 11
6.
Theor Appl Genet ; 137(7): 165, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38904787

RESUMO

KEY MESSAGE: A grain weight locus from Agropyron cristatum chromosome 5P increases grain weight in different wheat backgrounds and is localized to 5PL (bin 7-12). Thousand-grain weight is an important trait in wheat breeding, with a narrow genetic basis being the main factor limiting improvement. Agropyron cristatum, a wild relative of wheat, harbors many desirable genes for wheat improvement. Here, we found that the introduction of the 5P chromosome from A. cristatum into wheat significantly increased the thousand-grain weight by 2.55-7.10 g, and grain length was the main contributor to grain weight. An increase in grain weight was demonstrated in two commercial wheat varieties, indicating that the grain weight locus was not affected by the wheat background. To identify the chromosome segment harboring the grain weight locus, three A. cristatum 5P deletion lines, two wheat-A. cristatum 5P translocation lines and genetic populations of these lines were used to evaluate agronomic traits. We found that the translocation lines harboring the long arm of A. cristatum chromosome 5P (5PL) exhibited high grain weight and grain length, and the genetic locus associated with increased grain weight was mapped to 5PL (bin 7-12). An increase in grain weight did not adversely affect other agronomic traits in translocation line 5PT2, which is a valuable germplasm resource. Overall, we identified a grain weight locus from chromosome 5PL and provided valuable germplasm for improving wheat grain weight.


Assuntos
Agropyron , Mapeamento Cromossômico , Cromossomos de Plantas , Grão Comestível , Fenótipo , Melhoramento Vegetal , Locos de Características Quantitativas , Triticum , Triticum/genética , Triticum/crescimento & desenvolvimento , Agropyron/genética , Agropyron/crescimento & desenvolvimento , Cromossomos de Plantas/genética , Grão Comestível/genética , Grão Comestível/crescimento & desenvolvimento , Sementes/crescimento & desenvolvimento , Sementes/genética , Introgressão Genética , Translocação Genética
7.
Diagn Pathol ; 19(1): 86, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38909266

RESUMO

BACKGROUND: Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL). CASE PRESENTATION: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion. CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.


Assuntos
Linfoma Folicular , Linfoma Plasmablástico , Translocação Genética , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/patologia , Linfoma Plasmablástico/diagnóstico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Linfonodos/patologia
9.
Genes (Basel) ; 15(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38927657

RESUMO

Chromosomal translocations can result in phenotypic effects of varying severity, depending on the position of the breakpoints and the rearrangement of genes within the interphase nucleus of the translocated chromosome regions. Balanced translocations are often asymptomatic phenotypically and are typically detected due to a decrease in fertility resulting from issues during meiosis. Robertsonian translocations are among the most common chromosomal abnormalities, often asymptomatic, and can persist in the population as a normal polymorphism. We serendipitously discovered a Robertsonian translocation between chromosome 21 and chromosome 22, which is inherited across three generations without any phenotypic effect, notably only in females. In situ hybridization with alpha-satellite DNAs revealed the presence of both centromeric sequences in the translocated chromosome. The reciprocal translocation resulted in a partial deletion of the short arm of both chromosomes 21, and 22, with the ribosomal RNA genes remaining present in the middle part of the new metacentric chromosome. The rearrangement did not cause alterations to the long arm. The spread of an asymptomatic heterozygous chromosomal polymorphism in a population can lead to mating between heterozygous individuals, potentially resulting in offspring with a homozygous chromosomal configuration for the anomaly they carry. This new karyotype may not produce phenotypic effects in the individual who presents it. The frequency of karyotypes with chromosomal rearrangements in asymptomatic heterozygous form in human populations is likely underestimated, and molecular karyotype by array Comparative Genomic Hybridization (array-CGH) analysis does not allow for the identification of this type of chromosomal anomaly, making classical cytogenetic analysis the preferred method for obtaining clear results on a karyotype carrying a balanced rearrangement.


Assuntos
Cromossomos Humanos Par 21 , Cromossomos Humanos Par 22 , Translocação Genética , Humanos , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 22/genética , Hibridização in Situ Fluorescente , Cariótipo , Cariotipagem , Fenótipo , Translocação Genética/genética
10.
Genes (Basel) ; 15(6)2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38927744

RESUMO

While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions.


Assuntos
Deficiências do Desenvolvimento , Translocação Genética , Humanos , Masculino , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Fatores ras de Troca de Nucleotídeo Guanina/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 5/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia
11.
Biochemistry (Mosc) ; 89(4): 637-652, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38831501

RESUMO

Molecular genetic analysis of tumor tissues is the most important step towards understanding the mechanisms of cancer development; it is also necessary for the choice of targeted therapy. The Hi-C (high-throughput chromatin conformation capture) technology can be used to detect various types of genomic variants, including balanced chromosomal rearrangements, such as inversions and translocations. We propose a modification of the Hi-C method for the analysis of chromatin contacts in formalin-fixed paraffin-embedded (FFPE) sections of tumor tissues. The developed protocol allows to generate high-quality Hi-C data and detect all types of chromosomal rearrangements. We have analyzed various databases to compile a comprehensive list of translocations that hold clinical importance for the targeted therapy selection. The practical value of molecular genetic testing is its ability to influence the treatment strategies and to provide prognostic insights. Detecting specific chromosomal rearrangements can guide the choice of the targeted therapies, which is a critical aspect of personalized medicine in oncology.


Assuntos
Formaldeído , Neoplasias , Inclusão em Parafina , Humanos , Neoplasias/genética , Neoplasias/patologia , Formaldeído/química , Translocação Genética , Fixação de Tecidos , Cromatina/genética , Cromatina/metabolismo , Cromatina/química
13.
Methods Mol Biol ; 2825: 213-237, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38913312

RESUMO

Three-dimensional structured illumination microscopy (3D-SIM) and fluorescence in situ hybridization on three-dimensional preserved cells (3D-FISH) have proven to be robust and efficient methodologies for analyzing nuclear architecture and profiling the genome's topological features. These methods have allowed the simultaneous visualization and evaluation of several target structures at super-resolution. In this chapter, we focus on the application of 3D-SIM for the visualization of 3D-FISH preparations of chromosomes in interphase, known as Chromosome Territories (CTs). We provide a workflow and detailed guidelines for sample preparation, image acquisition, and image analysis to obtain quantitative measurements for profiling chromosome topological features. In parallel, we address a practical example of these protocols in the profiling of CTs 9 and 22 involved in the translocation t(9;22) in Chronic Myeloid Leukemia (CML). The profiling of chromosome topological features described in this chapter allowed us to characterize a large-scale topological disruption of CTs 9 and 22 that correlates directly with patients' response to treatment and as a possible potential change in the inheritance systems. These findings open new insights into how the genome structure is associated with the response to cancer treatments, highlighting the importance of microscopy in analyzing the topological features of the genome.


Assuntos
Imageamento Tridimensional , Hibridização in Situ Fluorescente , Humanos , Hibridização in Situ Fluorescente/métodos , Imageamento Tridimensional/métodos , Translocação Genética , Cromossomos/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Interfase/genética , Cromossomos Humanos/genética , Processamento de Imagem Assistida por Computador/métodos
14.
Nat Commun ; 15(1): 5110, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877018

RESUMO

Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.


Assuntos
Neoplasias , Proteínas de Fusão Oncogênica , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas c-ret , Translocação Genética , Humanos , Neoplasias/genética , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Linhagem Celular Tumoral
15.
Nat Commun ; 15(1): 5048, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871723

RESUMO

Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.


Assuntos
Cromatina , Iris , Linhagem , Translocação Genética , Humanos , Cromatina/metabolismo , Cromatina/genética , Iris/metabolismo , Masculino , Feminino , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 18/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Adulto , Doenças da Íris/genética , Doenças da Íris/metabolismo , Doenças da Íris/patologia , Ligação Genética
16.
Sci Adv ; 10(18): eadl1922, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38691604

RESUMO

The most common form of facioscapulohumeral dystrophy (FSHD1) is caused by a partial loss of the D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4. Patients with FSHD1 typically carry 1 to 10 D4Z4 repeats, whereas nonaffected individuals have 11 to 150 repeats. The ~150-kilobyte subtelomeric region of the chromosome 10q exhibits a ~99% sequence identity to the 4q, including the D4Z4 array. Nevertheless, contractions of the chr10 array do not cause FSHD or any known disease, as in most people D4Z4 array on chr10 is flanked by the nonfunctional polyadenylation signal, not permitting the DUX4 expression. Here, we attempted to correct the FSHD genotype by a CRISPR-Cas9-induced exchange of the chr4 and chr10 subtelomeric regions. We demonstrated that the induced t(4;10) translocation can generate recombinant genotypes translated into improved FSHD phenotype. FSHD myoblasts with the t(4;10) exhibited reduced expression of the DUX4 targets, restored PAX7 target expression, reduced sensitivity to oxidative stress, and improved differentiation capacity.


Assuntos
Cromossomos Humanos Par 10 , Cromossomos Humanos Par 4 , Genótipo , Proteínas de Homeodomínio , Distrofia Muscular Facioescapuloumeral , Fenótipo , Telômero , Humanos , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 4/genética , Sistemas CRISPR-Cas , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Distrofia Muscular Facioescapuloumeral/genética , Mioblastos/metabolismo , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Telômero/genética , Telômero/metabolismo , Translocação Genética
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(6): 753-757, 2024 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-38818564

RESUMO

OBJECTIVE: To carry out genetic analysis on two families with carriers of small terminal translocations using karyotyping analysis and genomic copy number variation sequencing (CNV-seq). METHODS: Two couples undergoing prenatal diagnosis at the Tianjin Central Hospital of Obstetrics and Gynecology respectively on April 12, 2020 and December 17, 2021 were selected as the study subjects. With informed consent, amniotic fluid and peripheral blood samples were collected and subjected to conventional karyotyping and CNV-seq analysis for the detection of chromosomal microdeletion/duplications. RESULTS: Both couples had given births to children with chromosomal aberrations previously, and both fetuses were found to have abnormal karyotypes. CNV-seq showed that they had harbored microdeletion/duplications, and their mothers had both carried balanced translocations involving terminal fragments of chromosomes. CONCLUSION: For fetuses with small chromosomal segmental abnormalities, their parental origin should be traced, and the diagnosis should be confirmed with combined genetic techniques.


Assuntos
Variações do Número de Cópias de DNA , Cariotipagem , Diagnóstico Pré-Natal , Humanos , Diagnóstico Pré-Natal/métodos , Feminino , Gravidez , Masculino , Adulto , Aberrações Cromossômicas , Translocação Genética , Testes Genéticos/métodos , Deleção Cromossômica
18.
Neuromuscul Disord ; 39: 24-29, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38714145

RESUMO

Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.


Assuntos
Distrofina , Distrofia Muscular de Duchenne , Translocação Genética , Distrofia Muscular de Duchenne/genética , Humanos , Masculino , Distrofina/genética , Feminino , Inversão Cromossômica/genética , Adulto , Criança
19.
Cancer Lett ; 594: 216980, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38797229

RESUMO

Acute myeloid leukemia (AML) is frequently linked to genetic abnormalities, with the t (8; 21) translocation, resulting in the production of a fusion oncoprotein AML1-ETO (AE), being a prevalent occurrence. This protein plays a pivotal role in t (8; 21) AML's onset, advancement, and recurrence, making it a therapeutic target. However, the development of drug molecules targeting AML1-ETO are markedly insufficient, especially used in clinical treatment. In this study, it was uncovered that Neratinib could significantly downregulate AML1-ETO protein level, subsequently promoting differentiation of t (8; 21) AML cells. Based on "differentiated active" probes, Neratinib was identified as a functional inhibitor against HNRNPA3 through covalent binding. The further studies demonstrated that HNRNPA3 function as a putative m6A reader responsible for recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. These findings not only contribute to a novel insight to the mechanism governing post-transcriptional modification of AML1-ETO transcript, but also suggest that Neratinib would be promising therapeutic potential for t (8; 21) AML treatment.


Assuntos
Diferenciação Celular , Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Quinolinas , Proteína 1 Parceira de Translocação de RUNX1 , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Quinolinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Precursores de RNA/metabolismo , Precursores de RNA/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Translocação Genética/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Processamento Alternativo/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Camundongos
20.
Front Endocrinol (Lausanne) ; 15: 1378635, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38737550

RESUMO

Objective: The objective of this study is to investigate the factors that influence the live birth rate (LBR) of the first single euploid frozen-thawed blastocyst transfer (FBT) cycles after preimplantation genetic testing for structural rearrangements (PGT-SR) in couples with balanced chromosomal translocations (BCT). Design: Single center, retrospective and observational study. Methods: A total of 336 PGT-SR and the first single euploid FBT cycles between July 2016 and December 2022 were included in this study. The patients were divided into two groups according to the live birth outcomes. The parameters of the study population, controlled ovarian stimulation cycles, and FBT cycles were analyzed. Multivariable binary logistic regression was performed to find the factors that affected the LBR. Results: The percentage of blastocysts at developmental stage Day 5 compared to Day 6 (51.8% vs. 30.8%; P<0.001) and with morphology ≥BB compared to

Assuntos
Criopreservação , Transferência Embrionária , Nascido Vivo , Taxa de Gravidez , Diagnóstico Pré-Implantação , Translocação Genética , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Adulto , Transferência Embrionária/métodos , Masculino , Diagnóstico Pré-Implantação/métodos , Coeficiente de Natalidade , Fertilização in vitro/métodos , Resultado da Gravidez , Blastocisto , Indução da Ovulação/métodos
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