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1.
Genet Med ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32015538

RESUMO

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. METHODS: We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. RESULTS: Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population. CONCLUSIONS: The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5-2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability.

2.
Acta Neuropathol ; 139(1): 157-174, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31664505

RESUMO

In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some neurofibromas. ATM-relevant DNA repair defects were also present in a subset of neurofibromas with ATM variants, and in some neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.

3.
Clin Genet ; 97(2): 264-275, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31573083

RESUMO

Children with neurofibromatosis type 1 (NF1) may exhibit an incomplete clinical presentation, making difficult to reach a clinical diagnosis. A phenotypic overlap may exist in children with other RASopathies or with other genetic conditions if only multiple café-au-lait macules (CALMs) are present. The syndromes that can converge in these inconclusive phenotypes have different clinical courses. In this context, an early genetic testing has been proposed to be clinically useful to manage these patients. We present the validation and implementation into diagnostics of a custom NGS panel (I2HCP, ICO-IMPPC Hereditary Cancer Panel) for testing patients with a clinical suspicion of a RASopathy (n = 48) and children presenting multiple CALMs (n = 102). We describe the mutational spectrum and the detection rates identified in these two groups of individuals. We identified pathogenic variants in 21 out of 48 patients with clinical suspicion of RASopathy, with mutations in NF1 accounting for 10% of cases. Furthermore, we identified pathogenic mutations mainly in the NF1 gene, but also in SPRED1, in more than 50% of children with multiple CALMs, exhibiting an NF1 mutational spectrum different from a group of clinically diagnosed NF1 patients (n = 80). An NGS panel strategy for the genetic testing of these two phenotype-defined groups outperforms previous strategies.

4.
Nat Cell Biol ; 21(8): 1041-1051, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31371824

RESUMO

Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Neoplasias do Endométrio/patologia , Organoides/patologia , Doenças Uterinas/patologia , Técnicas de Cultura de Células/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Doenças Uterinas/tratamento farmacológico , Doenças Uterinas/metabolismo
5.
Hum Mutat ; 40(10): 1760-1767, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31066482

RESUMO

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting approximately 1 in 2,000 newborns. Up to 5% of NF1 patients suffer from pseudarthrosis of a long bone (NF1-PA). Current treatments are often unsatisfactory, potentially leading to amputation. To gain more insight into the pathogenesis we cultured cells from PA tissue and normal-appearing periosteum of the affected bone for NF1 mutation analysis. PA cells were available from 13 individuals with NF1. Biallelic NF1 inactivation was identified in all investigated PA cells obtained during the first surgery. Three of five cases sampled during a later intervention showed biallelic NF1 inactivation. Also, in three individuals, we examined periosteum-derived cells from normal-appearing periosteum proximal and distal to the PA. We identified the same biallelic NF1 inactivation in the periosteal cells outside the PA region. These results indicate that NF1 inactivation is required but not sufficient for the development of NF1-PA. We observed that late-onset NF1-PA occurs and is not always preceded by congenital bowing. Furthermore, the failure to identify biallelic inactivation in two of five later interventions and one reintervention with a known somatic mutation indicates that NF1-PA can persist after the removal of most NF1 negative cells.

6.
Neuro Oncol ; 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30722027

RESUMO

Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly-aggressive soft-tissue sarcoma, often arising from pre-existing benign plexiform neurofibromas (PN) and atypical neurofibromas (ANF). ANF are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. Methods: In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of three MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of five ANFs and five MPNSTs. Results: We identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED or SUZ12 were frequently mutated, deleted or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3 and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only. Conclusions: The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction, cell cycle and pluripotency self-renewal genes.

8.
Pediatr Dermatol ; 35(3): e186-e188, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29493003

RESUMO

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.


Assuntos
Anormalidades Múltiplas/diagnóstico , Classe I de Fosfatidilinositol 3-Quinases/genética , Lipoma/diagnóstico , Megalencefalia/diagnóstico , Anormalidades Musculoesqueléticas/diagnóstico , Nevo/diagnóstico , Dermatopatias Vasculares/diagnóstico , Telangiectasia/congênito , Malformações Vasculares/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Sequência de Bases , Broncodilatadores/uso terapêutico , Diagnóstico Diferencial , Nutrição Enteral , Humanos , Imunossupressores/uso terapêutico , Recém-Nascido , Lipoma/genética , Lipoma/terapia , Masculino , Megalencefalia/genética , Megalencefalia/terapia , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Mutação , Nevo/genética , Nevo/terapia , Fenótipo , Respiração Artificial/métodos , Sirolimo/uso terapêutico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/terapia , Telangiectasia/diagnóstico , Telangiectasia/genética , Telangiectasia/terapia , Malformações Vasculares/genética , Malformações Vasculares/terapia
9.
Neuro Oncol ; 20(6): 818-825, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29409029

RESUMO

Background: Neurofibromatosis 1 (NF1) leads to the development of benign and malignant peripheral nerve sheath tumors (MPNST). MPNST have been described to develop in preexisting benign plexiform neurofibromas (PN) and have a poor prognosis. Atypical neurofibromas (ANF) were recently described as precursor lesions for MPNST, making early detection and management of ANF a possible strategy to prevent MPNST. We aimed to clinically characterize ANF and identify management approaches. Methods: We analyzed clinical, imaging, and pathology findings of all patients with NF1 and ANF at 3 institutions. Results: Sixty-three patients had 76 ANF (32M/31F; median age 27.1 y). On MRI, most ANF appeared as distinct nodular lesions and were 18F-fluorodeoxyglucose (FDG) avid. Forty-six ANF were associated with pain, 19 with motor weakness, 45 were palpable or visible, and 13 had no clinical signs. Completely resected ANF (N = 57) have not recurred (median follow-up, 4.1 y; range, 0-14 y). Four ANF transformed into MPNST and 17 patients had a history of MPNST in a different location than was their ANF. Conclusions: Growth of distinct nodular lesions, pain, and FDG-PET avidity should raise concern for ANF in NF1. Patients with ANF are at greater risk for development of MPNST. Complete resection of ANF may prevent development of MPNST.


Assuntos
Imagem por Ressonância Magnética/métodos , Neurofibroma/patologia , Neurofibromatose 1/patologia , Neurofibrossarcoma/patologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neurofibroma/complicações , Neurofibroma/diagnóstico por imagem , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/etiologia , Neurofibrossarcoma/diagnóstico por imagem , Neurofibrossarcoma/etiologia , Prognóstico , Adulto Jovem
10.
Annu Rev Genomics Hum Genet ; 18: 115-142, 2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28859574

RESUMO

The Ras-MAPK and PI3K-AKT-mTOR signaling cascades were originally identified as cancer regulatory pathways but have now been demonstrated to be critical for synaptic plasticity and behavior. Neurodevelopmental disorders arising from mutations in these pathways exhibit related neurological phenotypes, including cognitive dysfunction, autism, and intellectual disability. The downstream targets of these pathways include regulation of transcription and protein synthesis. Other disorders that affect protein translation include fragile X syndrome (an important cause of syndromal autism), and other translational regulators are now also linked to autism. Here, we review how mechanisms of synaptic plasticity have been revealed by studies of mouse models for Ras-MAPK, PI3K-AKT-mTOR, and translation regulatory pathway disorders. We discuss the face validity of these mouse models and review current progress in clinical trials directed at ameliorating cognitive and behavioral symptoms.


Assuntos
Disfunção Cognitiva/fisiopatologia , Deficiência Intelectual/metabolismo , Deficiência Intelectual/psicologia , Plasticidade Neuronal , Transdução de Sinais , Animais , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Humanos , Deficiência Intelectual/fisiopatologia , Camundongos , Serina-Treonina Quinases TOR
12.
Eur J Pediatr ; 175(9): 1193-1198, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27519821

RESUMO

UNLABELLED: A strong relationship between congenital pseudarthrosis of the tibia (CPT) and neurofibromatosis type 1 (NF1) has been suggested, but prevalence varies widely throughout the literature and the criteria used for diagnosis are very heterogeneous. Literature focus is mainly on treatment and no specific review on the prevalence of NF1 has been published. Based on our own observations, we hypothesized the prevalence of NF1 in patients with CPT to be higher than what is previously accepted. We conducted a comprehensive literature review on this topic and compared results with our study population. Twenty-one out of twenty-five patients in the study population matched the NIH diagnostic criteria for NF1 (84.0 %, CI95 = 69.6-98.4 %). These results are higher than the prevalence reported in the literature (55.4 %, CI95 = 50.4-60.4 %). CONCLUSIONS: The prevalence of NF1 in patients with CPT might be higher than what is reported until now because the criteria of NF1 generally appear only after the diagnosis of CPT. We propose a repeat meticulous examination and a multidisciplinary approach with a clinical genetic counseling in all CPT patients. WHAT IS KNOWN: • Congenital pseudarthrosis of the tibia and neurofibromatosis type 1 are closely related. • Literature focus is mainly on treatment and little epidemiologic research is available. What is New: • Prevalence of neurofibromatosis type 1 in patient with congenital pseudarthrosis of the tibia might be higher than what is reported until now. • A multidisciplinary approach with meticulous clinical examination and genetic counseling might lead to an earlier diagnosis of neurofibromatosis type 1 in patients with congenital pseudarthrosis of the tibia.


Assuntos
Neurofibromatose 1/epidemiologia , Pseudoartrose/congênito , Fraturas da Tíbia/congênito , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neurofibromatose 1/diagnóstico , Prevalência , Estudos Retrospectivos , Adulto Jovem
13.
J Craniomaxillofac Surg ; 44(8): 1054-60, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27316856

RESUMO

Giant cell granuloma (GCG) of the jaw is a rare, well-known feature of neurofibromatosis type 1 (NF1), an inborn multisystem disorder. Recently, the development of GCG in NF1 was attributed to second hit mutations in the NF1 gene. The treatment of GCG is pragmatic with a preference for local curettage of lytic osseous areas. This report describes the surgical therapy of an NF1-affected female with multilocular mandibular GCG and hypodontia who additionally suffered from a brain tumour and Hashimoto's thyroiditis. Although local recurrence of GCG was noted, augmentation of the curetted cavities with a bone substitute in successive interventions successfully restored the extensive periradicular local defects and stabilised the teeth. A meticulous in vitro study of the GCG specimen revealed a second hit mutation in the NF1 gene in the GCG spindle-cells. This study contributes to the increasing knowledge of the molecular basis for GCG in the jaw of NF1 patients, indicating that it is a neoplasm.


Assuntos
Genes da Neurofibromatose 1 , Granuloma de Células Gigantes/genética , Doenças Mandibulares/genética , Mutação , Adolescente , Substitutos Ósseos , Neoplasias Encefálicas/complicações , Tomografia Computadorizada de Feixe Cônico , Feminino , Granuloma de Células Gigantes/diagnóstico por imagem , Granuloma de Células Gigantes/cirurgia , Humanos , Processamento de Imagem Assistida por Computador , Doenças Mandibulares/diagnóstico por imagem , Doenças Mandibulares/cirurgia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Radiografia Panorâmica , Recidiva
14.
J Biol Chem ; 291(7): 3124-34, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26635368

RESUMO

Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120(GAP). Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome.


Assuntos
Manchas Café com Leite/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Modelos Moleculares , Mutação de Sentido Incorreto , Neurofibromatose 1/genética , Neurofibromina 1/metabolismo , Mutação Puntual , Sistema A de Transporte de Aminoácidos , Manchas Café com Leite/metabolismo , Manchas Café com Leite/fisiopatologia , Fator de Crescimento Epidérmico/metabolismo , Feminino , Genes Reporter , Estudos de Associação Genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinética , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Neurofibromatose 1/metabolismo , Neurofibromatose 1/fisiopatologia , Neurofibromina 1/química , Neurofibromina 1/genética , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas p21(ras)/agonistas , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo
15.
Gastroenterology ; 149(4): 1017-29.e3, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26116798

RESUMO

BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Resistencia a Medicamentos Antineoplásicos , Testes Genéticos , Mutação em Linhagem Germinativa , Linfócitos/efeitos dos fármacos , Instabilidade de Microssatélites , Síndromes Neoplásicas Hereditárias/diagnóstico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Células CACO-2 , Estudos de Casos e Controles , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Células HCT116 , Hereditariedade , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Endonuclease PMS2 de Reparo de Erro de Pareamento , Reação em Cadeia da Polimerase Multiplex , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Proteínas Nucleares/genética , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Transfecção , Adulto Jovem
16.
BMC Med Genet ; 16: 6, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25928347

RESUMO

BACKGROUND: Keratinocytic epidermal nevus syndrome (KENS) is a complex disorder not only characterized by the presence of epidermal nevi but also by abnormalities in the internal organ systems. A small number of cases with KENS are molecularly characterized and reported in the literature with somatic activating RAS, FGFR3 and PIK3CA mutations. CASE PRESENTATION: In this study we present a patient with hyper- and hypopigmented regions, verrucous pigmented skin lesions and a paravertebral conglomerate tumour at the level of the cervical and thoracic spine. A large lipomatous dumbbell tumour caused atrophy of the spinal cord with progressive paraparesis. We identified a mosaic c.35G > A (p.Gly12Asp) KRAS mutation in the pigmented verrucous epidermal nevus tissue, the intraneural schwann cells and the lipoma. The c.35G > A (p.Gly12Asp) KRAS mutation was absent in the peripheral blood leukocytes. CONCLUSION: We conclude that KENS, the intraneural Schwann cell proliferation and the lipoma in this individual were caused by a postzygotic and mosaic activating c.35G > A (p.Gly12Asp) KRAS mutation.


Assuntos
Lipoma/complicações , Mutação , Proteínas Proto-Oncogênicas/genética , Células de Schwann/patologia , Proteínas ras/genética , Adolescente , Proliferação de Células , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Nevo/complicações , Nevo/genética , Nevo/patologia , Proteínas Proto-Oncogênicas p21(ras) , Dermatopatias/complicações , Dermatopatias/genética , Dermatopatias/patologia , Adulto Jovem
17.
Nature ; 514(7521): 247-51, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25119042

RESUMO

The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Nucleares/antagonistas & inibidores , Complexo Repressor Polycomb 2/deficiência , Fatores de Transcrição/antagonistas & inibidores , Transcrição Genética , Proteínas ras/metabolismo , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Proteínas de Ciclo Celular , Morte Celular/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Cromatina/genética , Cromatina/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/patologia , Neoplasias da Bainha Neural/tratamento farmacológico , Neoplasias da Bainha Neural/genética , Neoplasias da Bainha Neural/patologia , Neurofibromina 1/deficiência , Neurofibromina 1/genética , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Triazóis/farmacologia , Triazóis/uso terapêutico , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas ras/antagonistas & inibidores
18.
Genome Biol ; 15(6): R80, 2014 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-24958239

RESUMO

BACKGROUND: Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. RESULTS: We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. CONCLUSIONS: Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.


Assuntos
Pontos de Quebra do Cromossomo , Mutagênese Insercional , Retroelementos , Sequência de Bases , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Genoma Humano , Humanos , Neurofibromatose 1/genética , Neurofibromina 1/genética , Complexo Repressor Polycomb 2/genética , Deleção de Sequência , Telômero/genética
19.
Genet Med ; 16(6): 448-59, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24232412

RESUMO

PURPOSE: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. METHODS: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions. RESULTS: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. CONCLUSION: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.


Assuntos
Manchas Café com Leite/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Neoplasias Ósseas/genética , Manchas Café com Leite/patologia , Células Cultivadas , Criança , Pré-Escolar , Cromograninas , Feminino , Fibroma/genética , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Razão de Masculinidade , Adulto Jovem
20.
PLoS One ; 8(11): e81791, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24303071

RESUMO

We recently reported that duplication of the E3 ubiquitin ligase HUWE1 results in intellectual disability (ID) in male patients. However, the underlying molecular mechanism remains unknown. We used Drosophila melanogaster as a model to investigate the effect of increased HUWE1 levels on the developing nervous system. Similar to the observed levels in patients we overexpressed the HUWE1 mRNA about 2-fold in the fly. The development of the mushroom body and neuromuscular junctions were not altered, and basal neurotransmission was unaffected. These data are in agreement with normal learning and memory in the courtship conditioning paradigm. However, a disturbed branching phenotype at the axon terminals of the dorsal cluster neurons (DCN) was detected. Interestingly, overexpression of HUWE1 was found to decrease the protein levels of dishevelled (dsh) by 50%. As dsh as well as Fz2 mutant flies showed the same disturbed DCN branching phenotype, and the constitutive active homolog of ß-catenin, armadillo, could partially rescue this phenotype, our data strongly suggest that increased dosage of HUWE1 compromises the Wnt/ß-catenin pathway possibly by enhancing the degradation of dsh.


Assuntos
Axônios/metabolismo , Deficiência Intelectual/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Via de Sinalização Wnt , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Drosophila , Expressão Gênica , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Aprendizagem , Memória , Corpos Pedunculados/metabolismo , Corpos Pedunculados/fisiopatologia , Junção Neuromuscular/metabolismo , Neurônios/metabolismo , Transmissão Sináptica , Proteínas Supressoras de Tumor
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