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


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.

Anat Sci Educ ; 8(2): 166-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24920370


One in six Americans is currently affected by neurologic disease. As the United States population ages, the number of neurologic complaints is expected to increase. Thus, there is a pressing need for more neurologists as well as more neurology training in other specialties. Often interest in neurology begins during medical school, so improving education in medical neural courses is a critical step toward producing more neurologists and better neurology training in other specialists. To this end, a novel applied neuroanatomy elective was designed at the University of Texas Health Science Center at San Antonio (UTHSCSA) to complement the traditional first-year medical neuroscience course and promote engagement and deep learning of the material with a focus on neurosensory pathways. The elective covered four neurosensory modalities (proprioception/balance, vision, auditory, and taste/olfaction) over four sessions, each with a short classroom component and a much longer activity component. At each session, students reviewed the neurosensory pathways through structured presentations and then applied them to preplanned interactive activities, many of which allowed students to utilize their artistic talents. Students were required to complete subjective pre-course and post-course surveys and reflections. The survey results and positive student comments suggest that the elective was a valuable tool when used in parallel with the traditional medical neuroscience course in promoting engagement and reinforcement of the neurosensory material.

Anatomia Artística/educação , Educação de Graduação em Medicina/métodos , Sistema Nervoso/anatomia & histologia , Neuroanatomia/educação , Sensação , Estudantes de Medicina/psicologia , Ensino/métodos , Percepção Auditiva , Currículo , Avaliação Educacional , Escolaridade , Humanos , Equilíbrio Postural , Aprendizagem Baseada em Problemas , Avaliação de Programas e Projetos de Saúde , Propriocepção , Faculdades de Medicina , Olfato , Inquéritos e Questionários , Paladar , Texas , Percepção Visual
Mol Reprod Dev ; 78(12): 906-19, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21919107


The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations. The lacI transgenic mouse can be used to study paternal age effects, and in this system, the prevalence of de novo mutations increases in the male germline at old ages. Mutagenesis is linked with DNA repair capacity, and base excision repair (BER), which can ameliorate spontaneous DNA damage, decreases in nuclear extracts of spermatogenic cells from old mice. Mice heterozygous for a null allele of the Apex1 gene, which encodes apurinic/apyrimidinic endonuclease I (APEN), an essential BER enzyme, display an accelerated increase in spontaneous germline mutagenesis early in life. Here, the consequences of lifelong reduction of APEN on genetic instability in the male germline were examined, for the first time, at middle and old ages. Mutant frequency increased earlier in spermatogenic cells from Apex1(+/-) mice (by 6 months of age). Nuclear DNA damage increased with age in the spermatogenic lineage for both wild-type and Apex1(+/-) mice. By old age, mutant frequencies were similar for wild-type and APEN-deficient mice. Mitochondrial genome repair also depends on APEN, and novel analysis of mitochondrial DNA (mtDNA) damage revealed an increase in the Apex1(+/-) spermatogenic cells by middle age. Thus, Apex1 heterozygosity results in accelerated damage to mtDNA and spontaneous mutagenesis, consistent with an essential role for APEN in maintaining nuclear and mtDNA integrity in spermatogenic cells throughout life.

Dano ao DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA/genética , Espermatogênese/genética , Espermatozoides/fisiologia , Fatores Etários , Animais , Apoptose , Núcleo Celular/genética , DNA/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Heterozigoto , Modelos Logísticos , Masculino , Camundongos , Camundongos Transgênicos , Mutagênese/genética , Espermatozoides/química
Biol Reprod ; 83(6): 979-87, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20739667


During the first wave of spermatogenesis, and in response to ionizing radiation, elevated mutant frequencies are reduced to a low level by unidentified mechanisms. Apoptosis is occurring in the same time frame that the mutant frequency declines. We examined the role of apoptosis in regulating mutant frequency during spermatogenesis. Apoptosis and mutant frequencies were determined in spermatogenic cells obtained from Bax-null or Trp53-null mice. The results showed that spermatogenic lineage apoptosis was markedly decreased in Bax-null mice and was accompanied by a significantly increased spontaneous mutant frequency in seminiferous tubule cells compared to that of wild-type mice. Apoptosis profiles in the seminiferous tubules for Trp53-null were similar to control mice. Spontaneous mutant frequencies in pachytene spermatocytes and in round spermatids from Trp53-null mice were not significantly different from those of wild-type mice. However, epididymal spermatozoa from Trp53-null mice displayed a greater spontaneous mutant frequency compared to that from wild-type mice. A greater proportion of spontaneous transversions and a greater proportion of insertions/deletions 15 days after ionizing radiation were observed in Trp53-null mice compared to wild-type mice. Base excision repair activity in mixed germ cell nuclear extracts prepared from Trp53-null mice was significantly lower than that for wild-type controls. These data indicate that BAX-mediated apoptosis plays a significant role in regulating spontaneous mutagenesis in seminiferous tubule cells obtained from neonatal mice, whereas tumor suppressor TRP53 plays a significant role in regulating spontaneous mutagenesis between postmeiotic round spermatid and epididymal spermatozoon stages of spermiogenesis.

Mutagênese , Espermatogênese , Espermatozoides/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Proteína X Associada a bcl-2/fisiologia , Envelhecimento , Animais , Animais Recém-Nascidos , Apoptose , Reparo do DNA , Raios gama/efeitos adversos , Marcação In Situ das Extremidades Cortadas , Óperon Lac , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese/efeitos da radiação , Túbulos Seminíferos/citologia , Túbulos Seminíferos/efeitos da radiação , Espermatogênese/efeitos da radiação , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Irradiação Corporal Total/efeitos adversos , Proteína X Associada a bcl-2/genética
Mutat Res ; 615(1-2): 98-110, 2007 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-17208258


Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF=4.70) when compared to normal peripheral nerve and brain (MF=2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

Genes da Neurofibromatose 1 , Mutação , Neurofibromatose 1/genética , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Genes p53 , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Neoplasias da Bainha Neural/genética , Fenótipo , Baço/metabolismo
Cancer Cell ; 7(1): 65-75, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15652750


Benign neurofibromas and malignant peripheral nerve sheath tumors are serious complications of neurofibromatosis type 1. The epidermal growth factor receptor is not expressed by normal Schwann cells, yet is overexpressed in subpopulations of Nf1 mutant Schwann cells. We evaluated the role of EGFR in Schwann cell tumorigenesis. Expression of EGFR in transgenic mouse Schwann cells elicited features of neurofibromas: Schwann cell hyperplasia, excess collagen, mast cell accumulation, and progressive dissociation of non-myelin-forming Schwann cells from axons. Mating EGFR transgenic mice to Nf1 hemizygotes did not enhance this phenotype. Genetic reduction of EGFR in Nf1(+/-);p53(+/-) mice that develop sarcomas significantly improved survival. Thus, gain- and loss-of-function experiments support the relevance of EGFR to peripheral nerve tumor formation.

Receptores ErbB/metabolismo , Neurofibroma/metabolismo , Neurofibromatose 1/metabolismo , Neurofibromatose 1/patologia , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Células de Schwann/fisiologia , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/genética , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Animais , Células Cultivadas , Receptores ErbB/genética , Fibrose , Humanos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias de Tecido Nervoso/genética , Neoplasias de Tecido Nervoso/metabolismo , Neoplasias de Tecido Nervoso/patologia , Neurofibroma/genética , Neurofibroma/patologia , Neurofibromatose 1/genética , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Nervos Periféricos/ultraestrutura , Células de Schwann/citologia , Transdução de Sinais/fisiologia , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo