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1.
Braz J Med Biol Res ; 52(6): e8424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141090

RESUMO

Although rare, CALM/AF10 is a chromosomal rearrangement found in immature T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia, and mixed phenotype acute leukemia of T/myeloid lineages with poor prognosis. Moreover, this translocation is detected in 50% of T-ALL patients with gamma/delta T cell receptor rearrangement, frequently associated with low expression of transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). However, the relevance of CEBPA low expression for CALM/AF10 leukemogenesis has not yet been evaluated. We generated double mutant mice, which express the Lck-CALM/AF10 fusion gene and are haploinsufficient for the Cebpa gene. To characterize the hematopoiesis, we quantified hematopoietic stem cells, myeloid progenitor cells, megakaryocyte-erythrocyte progenitor cells, common myeloid progenitor cells, and granulocyte-macrophage progenitor cells. No significant difference was detected in any of the progenitor subsets. Finally, we tested if Cebpa haploinsufficiency would lead to the expansion of Mac-1+/B220+/c-Kit+ cells proposed as the CALM/AF10 leukemic progenitor. Less than 1% of bone marrow cells expressed Mac-1, B220, and c-Kit with no significant difference between groups. Our results showed that the reduction of Cebpa gene expression in Lck-CALM/AF10 mice did not affect their hematopoiesis or induce leukemia. Our data corroborated previous studies suggesting that the CALM/AF10 leukemia-initiating cells are early progenitors with lymphoid/myeloid differentiating potential.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Haploinsuficiência/genética , Hematopoese/genética , Leucemia Mieloide Aguda/genética , Doença Aguda , Animais , Citometria de Fluxo , Genótipo , Camundongos , Camundongos Transgênicos , Fenótipo , Fatores de Transcrição/genética , Translocação Genética/genética
2.
Taiwan J Obstet Gynecol ; 58(2): 292-295, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30910156

RESUMO

OBJECTIVES: To present the prenatal findings and the molecular cytogenetic analyses of a de novo interstitial deletion of 1q23.3 encompassing PBX1 gene. CASE REPORT: A 32-year-old woman (gravida 1, para 0) underwent amniocentesis at 26 weeks' gestation because of constant small fetal kidneys on prenatal ultrasound. Chromosome microarray analysis (CMA) detected a de novo deletion of 1.871 Mb at 1q23.3. The deletion encompassed 2 genes of PBX1 and LMX1A. PBX1 haploinsufficiency had been reported to lead syndromic congenital anomalies of kidney and urinary tract (CAKUT) in humans. Furthermore, at 31 weeks' gestation, borderline oligohydramnios and restricted fetal dimensions were revealed. Ultimately, the pregnancy was terminated at 32 weeks with a 1500-g female fetus presenting polydactyl of left hand. CONCLUSIONS: The shared phenotypes between this case and the previously published prenatal cases demonstrate that loss of function mutation in PBX1 should be suspicious in fetus with bilateral renal hypoplasia, oligohydramnios and intrauterine growth retardation (IUGR).


Assuntos
Deleção Cromossômica , Haploinsuficiência/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Aborto Eugênico , Adulto , Amniocentese , Análise Citogenética , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/embriologia , Gravidez , Sindactilia/genética , Ultrassonografia Pré-Natal
3.
Nature ; 566(7743): 275-278, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700905

RESUMO

Genetic instability, a heritable increase in the rate of genetic mutation, accelerates evolutionary adaptation1 and is widespread in cancer2,3. In mammals, instability can arise from damage to both copies of genes involved in DNA metabolism and cell cycle regulation4 or from inactivation of one copy of a gene whose product is present in limiting amounts (haploinsufficiency5); however, it has proved difficult to determine the relative importance of these two mechanisms. In Escherichia coli6, the application of repeated, strong selection enriches for genetic instability. Here we have used this approach to evolve genetic instability in diploid cells of the budding yeast Saccharomyces cerevisiae, and have isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations; engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivated one copy of haploinsufficient genes were more common than those that dominantly altered the function of the mutated gene copy. The mutated genes were enriched for genes functioning in transport, protein quality control, and DNA metabolism, and have revealed new targets for genetic instability7-11, including essential genes. Although only a minority (10 out of 57 genes with orthologues or close homologues) of the targets we identified have homologous human genes that have been implicated in cancer2, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near-haploid human cell line; five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologues initiate genetic instability in cancer.


Assuntos
Evolução Molecular , Instabilidade Genômica/genética , Heterozigoto , Modelos Genéticos , Mutação , Neoplasias/genética , Saccharomyces cerevisiae/genética , Linhagem Celular , Diploide , Haploinsuficiência/genética , Humanos , Mutagênese/genética , Taxa de Mutação , Mutação Puntual
4.
Gene ; 696: 33-39, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763665

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding, skin and mucosa telangiectasias, and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes, which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1), respectively, both belonging to the TGF-ß/BMP signaling pathway. In this work, we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family, all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact, transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression.


Assuntos
Endoglina/genética , Domínios Proteicos/genética , Telangiectasia Hemorrágica Hereditária/genética , Adulto , Criança , Cisteína/genética , Endoglina/metabolismo , Éxons/genética , Feminino , Haploinsuficiência/genética , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Dobramento de Proteína , Transdução de Sinais , Telangiectasia Hemorrágica Hereditária/patologia , Adulto Jovem
5.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
6.
Transl Psychiatry ; 9(1): 29, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664619

RESUMO

Deletions in the 15q11.2 region of the human genome are associated with neurobehavioral deficits, and motor development delay, as well as in some cases, symptoms of autism or schizophrenia. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) is one of the four genes contained within this locus and has been associated with other genetic forms of autism spectrum disorders (ASD). In mice, Cyfip1 haploinsufficiency leads to alteration of dendritic spine morphology and defects in synaptic plasticity, two pathophysiological hallmarks of mouse models of ASD. At the behavioral level, however, Cyfip1 haploinsufficiency leads to minor phenotypes, not directly relevant for 15q11.2 deletion syndrome or ASD. A fundamental question is whether neuronal phenotypes caused by the mutation of Cyfip1 are relevant for the human condition. Here, we describe a synaptic cluster of ASD-associated proteins centered on CYFIP1 and the adhesion protein Neuroligin-3. Cyfip1 haploinsufficiency in mice led to decreased dendritic spine density and stability associated with social behavior and motor learning phenotypes. Behavioral training early in development resulted in alleviating the motor learning deficits caused by Cyfip1 haploinsufficiency. Altogether, these data provide new insight into the neuronal and behavioral phenotypes caused by Cyfip1 mutation and proof-of-concept for the development of a behavioral therapy to treat phenotypes associated with 15q11.2 syndromes and ASD.


Assuntos
Transtorno do Espectro Autista/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Comportamento Social , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Aberrações Cromossômicas , Cromossomos Humanos Par 15/genética , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Distribuição Aleatória
7.
Transl Psychiatry ; 9(1): 24, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655503

RESUMO

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.


Assuntos
Transtorno do Espectro Autista/genética , Comportamento Animal , Haploinsuficiência/genética , Metiltransferases/genética , Neurônios/metabolismo , Animais , Transtorno do Espectro Autista/psicologia , Encéfalo/patologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Mutação
8.
Eur J Haematol ; 102(3): 203-209, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30578738

RESUMO

The molecular pathogenesis of deletion 5q (del(5q)) myelodysplastic syndrome (MDS) has recently been realized as a result of major advances in our understanding of the mechanisms responsible for clinical phenotype. Identification of commonly deleted genes such as RPS14, miRNA-145, HSPA9, CD78, and CSNK1a1 have elucidated the precise biological changes responsible for the anemia, leukopenia, and thrombocytosis that characterizes del(5q) MDS and highlighted the importance of allelic haploinsufficiency in the hematological phenotype. Recent elegant investigations have also identified a critical role of innate immune signaling in del(5q) pathogenesis. TP53 and Wnt/ß-catenin pathways have also been found to be involved in clonal expansion and progression of the disease as well as resistance and poor outcomes to available therapy. Understanding the molecular pathogenesis of the disease has provided a critical foundation in identifying the biological targets of lenalidomide in del(5q) MDS, which has led to the development of novel therapeutic agents in hematologic malignancies as well as potential alternative targets to exploit in patients who have failed lenalidomide treatment.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas/etiologia , Anemia/diagnóstico , Anemia/genética , Anemia/metabolismo , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Evolução Clonal/genética , Evolução Clonal/imunologia , Progressão da Doença , Haploinsuficiência/genética , Humanos , Imunidade Inata/genética , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/terapia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Ribossômicas/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt
9.
BMJ Case Rep ; 20182018 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-29680795

RESUMO

We present a case of monocytopaenia and mycobacteria-related infection (MonoMac) syndrome in a 30-year-old man of Indian origin. The clinical diagnosis of GATA2 haploinsufficiency was suspected after an unusual neurological presentation on a background of myelodysplastic syndrome and childhood pulmonary tuberculosis. The patient had a longitudinally extensive spinal cord lesion and a lesion in the medulla. No obvious infective cause for the spinal cord MRI abnormality was found, and the lesions were presumed to be inflammatory in nature. The family history consisted of autosomal dominant clinical features suggestive of GATA2 haploinsufficiency. Genetic testing in peripheral leucocytes revealed a pathogenic mutation in GATA2 This is the first-ever published case of possible MonoMac syndrome with a neurological presentation. The case highlights the rarity and complexity of the diagnosis and the clinical sequelae that ensued with the patient dying of gram-negative septicaemia while receiving intravenous steroid therapy for the spinal cord lesion.


Assuntos
Fator de Transcrição GATA2/genética , Haploinsuficiência/genética , Síndromes de Imunodeficiência/complicações , Infecções por Mycobacterium/complicações , Síndromes Mielodisplásicas/complicações , Doenças da Medula Espinal/complicações , Adulto , Diagnóstico Diferencial , Evolução Fatal , Infecções por Bactérias Gram-Negativas/complicações , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/microbiologia , Imagem por Ressonância Magnética/métodos , Masculino , Mutação , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/microbiologia , Síndromes Mielodisplásicas/microbiologia , Síndromes Mielodisplásicas/patologia , Sepse/complicações , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/tratamento farmacológico , Doenças da Medula Espinal/patologia , Tuberculose Pulmonar/complicações
10.
G3 (Bethesda) ; 8(4): 1299-1314, 2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29472308

RESUMO

Genetic interaction analysis is a powerful approach to the study of complex biological processes that are dependent on multiple genes. Because of the largely diploid nature of the human fungal pathogen Candida albicans, genetic interaction analysis has been limited to a small number of large-scale screens and a handful for gene-by-gene studies. Complex haploinsufficiency, which occurs when a strain containing two heterozygous mutations at distinct loci shows a phenotype that is distinct from either of the corresponding single heterozygous mutants, is an expedient approach to genetic interactions analysis in diploid organisms. Here, we describe the construction of a barcoded-library of 133 heterozygous TF deletion mutants and deletion cassettes for designed to facilitate complex haploinsufficiency-based genetic interaction studies of the TF networks in C. albicans We have characterized the phenotypes of these heterozygous mutants under a broad range of in vitro conditions using both agar-plate and pooled signature tag-based assays. Consistent with previous studies, haploinsufficiency is relative uncommon. In contrast, a set of 12 TFs enriched in mutants with a role in adhesion were found to have altered competitive fitness at early time points in a murine model of disseminated candidiasis. Finally, we characterized the genetic interactions of a set of biofilm related TFs in the first two steps of biofilm formation, adherence and filamentation of adherent cells. The genetic interaction networks at each stage of biofilm formation are significantly different indicating that the network is not static but dynamic.


Assuntos
Candida albicans/genética , Candida albicans/patogenicidade , Haploinsuficiência/genética , Fatores de Transcrição/genética , Animais , Biofilmes , Candida albicans/crescimento & desenvolvimento , Candidíase/genética , Candidíase/microbiologia , Candidíase/patologia , Modelos Animais de Doenças , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Deleção de Genes , Biblioteca Gênica , Redes Reguladoras de Genes , Heterozigoto , Fenótipo , Plâncton/metabolismo , Plasmídeos/metabolismo , Fatores de Transcrição/metabolismo , Virulência/genética
11.
Balkan Med J ; 35(3): 272-274, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29219112

RESUMO

Background: Ovotesticular disorder is characterized by the presence of testicular and ovarian tissues in the same individual. Single gene mutations in SRY, SOX9, DMRT1 and DAX1 can lead to ovotesticular disorder of sexual development. Case Report: Herein, we report a 3-month-old phenotypically female baby in whom differentiated tissues of both Müllerian and Wolffian ducts were detected on pathological analysis of laparoscopic biopsy material. Chromosomal analysis observed 46,XY, der(9)t(3;9)(p25;p24) with deletion of 9p24.3p23 including the DMRT gene cluster and duplication of 3p26.3p24.3 on array comparative genomic hybridisation. Conclusion: In support of previous literature, we found that haploinsufficiency of the DMRT gene cluster leads to ovotesticular disorder of sexual development. In addition, we emphasize that array comparative genomic hybridisation is an important technique in the molecular diagnosis of ovotesticular disorder of sexual.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Haploinsuficiência/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Tionucleosídeos/genética , Trifosfato de Adenosina/genética , Feminino , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Família Multigênica , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Fatores de Transcrição SOX9 , Testículo
12.
Redox Biol ; 14: 88-99, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28888203

RESUMO

Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.


Assuntos
Células Endoteliais/metabolismo , Glutamato-Cisteína Ligase/genética , Glutationa/biossíntese , Animais , Biopterina/análogos & derivados , Biopterina/uso terapêutico , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/citologia , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose , Glutamato-Cisteína Ligase/deficiência , Haploinsuficiência/genética , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo
13.
Muscle Nerve ; 57(1): 150-156, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28093780

RESUMO

INTRODUCTION: Autosomal dominant haploinsufficiency of GATA2 causes monocytopenia and natural killer cell lymphopenia, resulting in predisposition to mycobacterial, fungal, and viral infections. METHODS: Herein we report on the clinical, serologic, electrophysiologic, and pathologic evaluations of a 29-year-old woman with GATA2 haploinsufficiency and active Epstein-Barr virus (EBV) infection complicated by subacute painful neuropathy. RESULTS: Nerve conduction and electromyography studies showed predominantly demyelinating sensorimotor polyradiculoneuropathy. Lumbar spine MRI showed thickening and enhancement of the cauda equina nerve roots. Serum and cerebrospinal fluid anti-IgG and IgM EBV capsid and nucleic acid antibodies were positive. Sural nerve biopsy showed microvasculitis and an increased frequency of fibers with segmental demyelination. Intravenous immunoglobulin and steroids improved the patient's neuropathy. CONCLUSION: GATA2 mutation-related immunodeficiency may predispose to EBV-associated subacute demyelinating polyradiculoneuropathy by both viral susceptibility and immune dysregulation. In patients who present in this manner, immunodeficiency syndromes should be considered when lymphomatous infiltration is excluded. Immunotherapy can be helpful. Muscle Nerve 57: 150-156, 2018.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Fator de Transcrição GATA2/genética , Haploinsuficiência/genética , Polirradiculoneuropatia/complicações , Polirradiculoneuropatia/genética , Adulto , Anticorpos Anti-Idiotípicos , Doenças Autoimunes do Sistema Nervoso/patologia , Biópsia , Eletromiografia , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Feminino , Humanos , Síndromes de Imunodeficiência , Imagem por Ressonância Magnética , Condução Nervosa , Exame Neurológico , Polirradiculoneuropatia/diagnóstico por imagem , Nervo Sural/patologia
14.
Am J Hum Genet ; 101(6): 985-994, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198724

RESUMO

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.


Assuntos
Proteína Morfogenética Óssea 2/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Nanismo/genética , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Animais , Osso e Ossos/embriologia , Criança , Pré-Escolar , Cromossomos Humanos Par 20/genética , Fissura Palatina/genética , Modelos Animais de Doenças , Feminino , Coração/embriologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Fator de Crescimento Transformador beta/genética
15.
Orphanet J Rare Dis ; 12(1): 183, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258554

RESUMO

CLINICAL DESCRIPTION: KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. The condition was named KBG syndrome after the initials of the last names of three original families reported in 1975. EPIDEMIOLOGY: The prevalence of KBG syndrome is not established. There are over 100 patients reported in the literature. It is likely that KBG syndrome is underreported due to incomplete recognition and very mild presentations of the disorder in some individuals. KBG syndrome is typically milder in females. ETIOLOGY: Causative variants in ANKRD11 have been identified in affected individuals. The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity. GENETIC COUNSELING: Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern. The syndrome displays inter- and intra-familial variability.


Assuntos
Anormalidades Múltiplas/metabolismo , Doenças do Desenvolvimento Ósseo/metabolismo , Deficiência Intelectual/metabolismo , Anormalidades Dentárias/metabolismo , Anormalidades Múltiplas/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Hibridização Genômica Comparativa , Facies , Feminino , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Humanos , Deficiência Intelectual/genética , Masculino , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Convulsões/genética , Convulsões/metabolismo , Anormalidades Dentárias/genética
16.
Am J Hum Genet ; 101(6): 1021-1033, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220674

RESUMO

ACTB encodes ß-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, ß-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic ß-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, ß-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Actinas/biossíntese , Adolescente , Adulto , Idoso , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Coloboma/genética , Facies , Feminino , Mutação da Fase de Leitura/genética , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Adulto Jovem
17.
Cell Rep ; 21(8): 2198-2211, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29166610

RESUMO

CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca2+ pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca2+ uptake and maintains intracellular Ca2+ homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC.


Assuntos
Cálcio/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/metabolismo , Haploinsuficiência/genética , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/genética , Homeostase/fisiologia , Humanos , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
18.
Nature ; 552(7683): 121-125, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29143824

RESUMO

T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.


Assuntos
Carcinogênese/genética , Genes Supressores de Tumor , Haploinsuficiência/genética , Linfoma de Células T/genética , Linfoma de Células T/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Animais , Células Cultivadas , Feminino , Humanos , Linfoma de Células T/metabolismo , Masculino , Camundongos , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/genética , Linfócitos T/metabolismo , Linfócitos T/patologia
19.
Mol Autism ; 8: 54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29034068

RESUMO

BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.


Assuntos
Transtorno do Espectro Autista/genética , Haploinsuficiência/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adolescente , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
20.
Toxicol Pathol ; 45(6): 774-785, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-29046139

RESUMO

The use of immunohistochemical (IHC) staining in determining and/or confirming the cellular origin of poorly differentiated sarcomas was evaluated in this study. Sarcomatous neoplasms were evaluated in a research study conducted in 2 strains of p53+/- haploinsufficient mice. The most common neoplasms were undifferentiated sarcomas, followed by osteosarcomas and rhabdomyosarcomas (RMSs). The RMSs were poorly differentiated and appeared similar to the pleomorphic, or adult type, RMS of humans. All sarcomas stained positive by IHC for the mesenchymal cell intermediate filament vimentin. The RMSs were identified by positive IHC staining for myogenin, a transcription factor specific to skeletal muscle. Osteosarcomas were easily identifiable on hematoxylin and eosin-stained slides; no generally accepted IHC stain specific for bone is presently available. Some of the undifferentiated sarcomas contained numerous macrophages that stained positive for F4/80, a macrophage marker; the positive-staining cells were considered to be infiltrating macrophages. One-third of the neoplasms observed in this study were associated with subcutaneous implanted electronic microchips used for animal identification. Based upon histopathologic evaluation and IHC staining, it was not possible to distinguish neoplasms associated with subcutaneous microchips from neoplasms not associated with microchips.


Assuntos
Haploinsuficiência/genética , Rabdomiossarcoma/patologia , Sarcoma Experimental/patologia , Proteína Supressora de Tumor p53/genética , Animais , Imuno-Histoquímica , Masculino , Camundongos Knockout , Rabdomiossarcoma/etiologia , Rabdomiossarcoma/genética , Sarcoma Experimental/etiologia , Sarcoma Experimental/genética
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