RESUMO
PURPOSE: Pineal anlage tumor is an extremely rare tumor which was considered as a subtype of pineovlatoma with an overall poor prognosis. This case-based review further summarize the clinical profile. METHODS: A patient with pineal anlage tumor was reported, her clinical data and gene analysis results were recorded. RESULTS: An 8-month-old girl, with an obvious enhancing pineal occupancy and obstructive hydrocephalus. Her histological and immunohistochemical findings contained rhabdomyoblastic, melanin pigment and cartilage island. The wholeexpme sequencing and genome-wide copy number variation sequencing were performed, no mutations associated with pineoblatoma as well as copy number variants were identified. In terms of treatment, our patient underwent subtotal resection without radiotherapy or chemotherapy, and the residual tumor enlarged 4 months after surgery. We have followed her up for 10 months, and the child is still alive. CONCLUSION: Surgery combined radiotherapy and chemotherapy is still the best treatment currently,and genetic testing for patients is necessary.
Assuntos
Neoplasias Encefálicas , Glândula Pineal , Pinealoma , Neoplasias Supratentoriais , Humanos , Criança , Feminino , Lactente , Neoplasias Encefálicas/cirurgia , Variações do Número de Cópias de DNA , Pinealoma/patologia , Glândula Pineal/cirurgia , Neoplasias Supratentoriais/patologiaRESUMO
Radiation-induced gastric injury is a serious adverse effect and reduces the efficacy of radiotherapy treatment. However, the mechanisms underlying radiation-induced stomach injury remain unclear. Here, mouse stomach and gastric epithelial cells were irradiated with different doses of X-ray radiation. The results showed that radiation induced gastric injury in vivo and in vitro. Differentially expressed functional mRNAs in irradiation-induced gastric tissues were screened from the Gene Expression Omnibus (GEO) database. We found that the expression of microtubule-associated serine/threonine kinase 1 (Mast1) was downregulated in mouse gastric tissues and gastric epithelial cells after irradiation. Furthermore, functional assays showed that knockdown of Mast1 inhibited growth and promoted apoptosis in gastric epithelial cells, while overexpression of Mast1 protected gastric epithelial cells from radiation damage. Mechanistically, Mast1 negatively regulated radiation-induced injury in gastric epithelial cells by inhibiting the activation of P38. The apoptosis caused by knockdown of Mast1 in gastric epithelial cells could be partially reversed by the P38 inhibitor SB203580. Moreover, data from several gastric cancer cell lines and online databases revealed that Mast1 was not involved in the development of gastric cancer. Collectively, our findings demonstrated that Mast1 is essential for radiation-induced gastric injury, providing a promising prognostic and therapeutic target.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Gástricas/patologia , Estômago/patologia , Raios X/efeitos adversos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Estômago/lesões , Estômago/metabolismo , Estômago/efeitos da radiação , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
We report the case of a Caucasian Spanish origin female who showed severe psychomotor developmental delay, hypotonia, strabismus, epilepsy, short stature, and poor verbal language development. Brain magnetic resonance imaging scans showed thickened corpus callosum, cortical malformations, and dilated and abnormal configuration of the lateral ventricles without hydrocephalus. Whole-exome sequence uncovered a de novo variant in the microtubule associated serine/threonine kinase 1 gene (MAST1; NM_014975.3:c.1565G>A:p.(Gly522Glu)) that encodes for the MAST1. Only 12 patients have been identified worldwide with 10 different variants in this gene: six patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations; two patients with microcephaly and cerebellar hypoplasia; two patients with autism, one patient with diplegia, and one patient with microcephaly and dysmorphism. Our patient shows a new phenotypic subtype defined by mega-corpus-callosum syndrome with cortical malformations without cerebellar hypoplasia. In conclusion, our data expand the phenotypic spectrum associated to MAST1 gene variants.
Assuntos
Agenesia do Corpo Caloso/genética , Cerebelo/anormalidades , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Malformações do Sistema Nervoso/genética , Proteínas Serina-Treonina Quinases/genética , Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/patologia , Cerebelo/patologia , Criança , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Nanismo/complicações , Nanismo/genética , Nanismo/patologia , Feminino , Humanos , Hidrocefalia/complicações , Hidrocefalia/genética , Hidrocefalia/patologia , Lactente , Masculino , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Microcefalia/complicações , Microcefalia/patologia , Hipotonia Muscular/complicações , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging features. The syndrome is caused by pathogenic variants in the MAST1 gene, which encodes a microtubule-associated protein that is predominantly expressed in postmitotic neurons in the developing nervous system. METHODS: Fetal DNA from umbilical cord blood samples and genomic DNA from peripheral blood lymphocytes were subjected to whole-exome sequencing. The potential causative variants were verified by Sanger sequencing. RESULTS: A 26-year-old primigravid woman was referred to our prenatal center at 25 weeks of gestation due to abnormal ultrasound findings in the brain of the fetus. The brain abnormalities included wide cavum septum pellucidum, shallow and incomplete bilateral lateral fissure cistern, bilateral dilated lateral ventricles, hyperplastic corpus callosum, lissencephaly, and cortical dysplasia. No obvious abnormalities were observed in the brainstem or cerebellum hemispheres, but the cerebellum vermis was small. Whole-exome sequencing identified a de novo, heterozygous missense variant, c.695T>C(p.Leu232Pro), in the MAST1 gene and a genetic diagnosis of mega-corpus-callosum syndrome was considered. CONCLUSION: This study is the first prenatal case of MAST1-related disorder reported in the Chinese population and has expanded the mutation spectrum of the MAST1 gene.
Assuntos
Vermis Cerebelar , Leucoencefalopatias , Malformações do Desenvolvimento Cortical , Malformações do Sistema Nervoso , Gravidez , Feminino , Humanos , Adulto , Vermis Cerebelar/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/anormalidades , Malformações do Desenvolvimento Cortical/genética , Feto/anormalidades , DNA , Deficiências do DesenvolvimentoRESUMO
OBJECTIVE: Heterozygous variations in microtubule-associated serine/threonine kinase 1 gene (MAST1) were recently described in the mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM, MIM 618273), revealing the importance of the MAST genes family in global brain development. To date, patients with MAST1 gene mutations were mostly young children with central nervous system involvement, impaired motor function, speech delay, and brain magnetic resonance imaging (MRI) abnormalities. Here, we report the clinical presentation of an adult patient with a rare and de novo MAST1 mutation with central hypogonadism that could extend this phenotype. METHODS: A panel of 333 genes involved in epilepsy or cortical development was sequenced in the described patient. Routine biochemical analyses were performed, and hormonal status was investigated. RESULT: We report a 22-year-old man with a de novo, heterozygous missense variant in MAST1 (Chr19(GRCh37):g.12975903G > A, NP_055790.1:p.Gly517Ser). He presented with an epileptic encephalopathy associated with cerebral malformations, short stature, hypogonadotropic hypogonadism, and secondary osteopenia. CONCLUSION: This is the first patient with MAST1 gene mutation described with central hypogonadism, which may be associated with the phenotype of MCCCHCM syndrome.
Assuntos
Hipogonadismo , Leucoencefalopatias , Malformações do Sistema Nervoso , Criança , Masculino , Humanos , Pré-Escolar , Adulto Jovem , Adulto , Malformações do Sistema Nervoso/genética , Leucoencefalopatias/genética , Mutação , Microtúbulos , Hipogonadismo/genéticaRESUMO
Intellectual disability (ID) is one of the most common developmental disorders characterized by a congenital limitation in intellectual functioning and adaptive behavior. More than 800 genes have been implicated so far in the pathogenesis of syndromic and non-syndromic ID conditions with the actual number is expected to be over two thousand. The advent of next-generation sequencing resulted in the identification of many novel ID genes with new genes are being reported on weekly basis. The level of evidence on ID genes varies with some of them being preliminary. MAST1 have been hinted at as being causative of ID but the evidence has been very sketchy. Extensive search of the literature identified three heterozygous de novo missense variants in MAST1 as possible causes of syndromic ID in three individuals where intellectual disability has been a major feature. Using exome sequencing, we identified a novel missense variant c.3539T>G, p.(Leu1180Arg) in MAST1 in an Emirati patient with intellectual disability, microcephaly, and dysmorphic features. In silico pathogenicity prediction analyses predict that all the four missense variants reported in this study are likely to be damaging. Immunostaining of cells expressing human MAST1 showed that majority large proportion of the expressed protein is colocalized the microtubule filaments in the cytoplasm. However, the identified variant c.3539T>G, p.(Leu1180Arg) as well as the other three variants seem to localize in a similar pattern to wild-type indicating a disease mechanism not involving mis-targeting. We, therefore, suggest that mutations in MAST1 should be considered as strong candidates for intellectual disability in humans.
Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Criança , Deficiências do Desenvolvimento/patologia , Células HEK293 , Células HeLa , Humanos , Deficiência Intelectual/patologia , Masculino , Transporte ProteicoRESUMO
Although 19p13.13 microdeletion syndrome has been consistently associated with intellectual disability, overgrowth, and macrocephaly, the underlying mechanisms remain unclear. MAST1, a member of the microtubule-associated serine/threonine kinase family, has been suggested as a potential candidate gene responsible for neurologic abnormalities in 19p13.13 microdeletion syndrome, but its role in nervous system development remains to be elucidated. Here, we investigated how MAST1 contributes to neuronal development. We report that MAST1 is upregulated during neuronal differentiation of the human neuroblastoma cell line, SH-SY5Y. Inhibition of MAST1 expression by RNA interference attenuated neuronal differentiation of SH-SY5Y cells. Cell cycle analyses revealed that MAST1-depleted cells did not undergo cell cycle arrest after RA treatment. Consistent with this observation, the number of EdU-positive cells significantly increased in MAST1 knockdown cells. Intriguingly, levels of P27, a cyclin-dependent kinase inhibitor, were also increased during neuronal differentiation, and MAST1 knockdown reduced the expression of P27. Moreover, reduced neuronal differentiation caused by MAST1 depletion was rescued partially by P27 overexpression in SH-SY5Y cells. Collectively, these results suggest that MAST1 influences nervous system development by affecting neuronal differentiation through P27.
Assuntos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Anormalidades Múltiplas/genética , Animais , Ciclo Celular , Diferenciação Celular , Linhagem Celular Tumoral , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Células-Tronco Neurais/fisiologia , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.
Assuntos
Agenesia do Corpo Caloso/genética , Cerebelo/anormalidades , Regulação da Expressão Gênica no Desenvolvimento/genética , Malformações do Desenvolvimento Cortical/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Malformações do Sistema Nervoso/genética , Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Animais , Animais Recém-Nascidos , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Cerebelo/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Humanos , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas do Tecido Nervoso/metabolismo , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico por imagem , Fator de Transcrição PAX6/metabolismoRESUMO
AIMS: In recent years, aberrant DNA methylation of specific CpG sites has been detected in many types of malignant tumors, and the epigenetic regulation of promoter CpG sites is considered an important mechanism underlying carcinogenesis. This study aimed to establish the epigenetics of the malignant transformation of malignant pheochromocytoma (PCC) and paraganglioma (PGL) by performing a methylation analysis. MATERIALS AND METHODS: Based on the results of the Infinium HumanMethylation450 BeadChip array using DNA samples of PCC/PGL patients, candidate CpG sites that were hyper/hypo-methylated in metastatic tumors relative to those in the primary tumors of 2 patients with malignant PCC/PGL were selected. The methylation levels of the chosen candidate CpG sites were evaluated quantitatively. RESULTS: Twelve CpG sites were selected as hypermethylated candidates, and 16 CpG sites were selected as hypomethylated candidates. Using two quantitative methylation analysis methods, one hypermethylated site (cg02119938) and one hypomethylated site (cg26870725) remained as candidates. These sites were related to ACSBG1 (acyl-CoA synthetase bubblegum family member 1) and MAST1 (microtubule-associated serine-threonine kinase 1), respectively. Immunohistochemical studies of ACSBG1 and MAST1 revealed that epigenetic changes in the malignant transformation of PCC/PGL might be associated with ACSBG1 silencing or MAST1 overexpression. CONCLUSIONS: Here, we report two noteworthy genes, ACSBG1 and MAST1; the aberrant promoter methylation/demethylation of these genes might be involved in their silencing/expression in malignant PCC/PGL. Further investigations are necessary to determine the role of ACSBG1 and/or MAST1 expression in malignant transformation and to establish pathological markers that can evaluate the malignant potential of PCC/PGL.