RESUMO
Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2), and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids). Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.
Assuntos
Anemia de Fanconi/genética , Linfoma não Hodgkin/genética , Proteínas Nucleares/genética , Rad51 Recombinase/genética , Proteínas Supressoras de Tumor/genética , Alelos , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Cromossomos/genética , Dano ao DNA/genética , Anemia de Fanconi/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Linfoma não Hodgkin/patologia , MutaçãoRESUMO
BACKGROUND: Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterised by progressive cerebellar ataxia, immunodeficiency, genetic instability, and cancer susceptibility. In addition, many patients suffer from growth failure. METHODS: We analyzed growth and IGF-1/BP3 levels of 24 A-T-patients compared with an age-matched group of healthy controls (n = 36). RESULTS: Ten (41.7%) A-T patients and none of healthy controls had an IGF-1 level below the 3rd percentile for age. The growth hormone (GH) stimulation tests revealed a severe GH deficiency with no increase of >5 ng/ml in six of the ten A-T patients. The IGF-1 generation tests revealed normal increases in IGF-1 values in all patients. CONCLUSION: Our results show that a disturbance in the GH/IGF-1 axis was present in 58.3% of A-T patients. Low levels of GH were the result of reduced central GH secretion. GH treatment may be a therapeutic option for A-T patients with severe growth failure.
Assuntos
Ataxia Telangiectasia/sangue , Estatura , Hormônio do Crescimento Humano/deficiência , Adolescente , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/patologia , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , MasculinoRESUMO
Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Adulto , Substituição de Aminoácidos , Proteínas Mutadas de Ataxia Telangiectasia/química , Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Neoplasias da Mama/genética , Cafeína/farmacologia , Criança , Éxons/genética , Feminino , Fase G2 , Heterozigoto , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Masculino , Testes para Micronúcleos , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias/genética , Exame Neurológico , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , Tolerância a Radiação/genética , Reparo de DNA por Recombinação/genética , Rabdomiossarcoma Embrionário/genética , Fase S , Análise de Sequência de DNARESUMO
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.
Assuntos
Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adolescente , Adulto , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Criança , Proteínas de Ligação a DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
Polycomb group (PcG) proteins are chromatin modifiers that are necessary for the maintenance and renewal of embryonic and adult stem cells. However, overexpression of the PcG protein, Bmi-1, causes lymphoma in transgenic mice. We show that Bmi-1 is up-regulated in Hodgkin lymphoma (HL) cells by the Epstein-Barr virus (EBV) oncogene latent membrane protein-1 (LMP1) and that this up-regulation is mediated by NF-kappaB signaling. We also show that Bmi-1 is up-regulated by NF-kappaB in EBV-negative HL cells. Down-regulation of LMP1 and Bmi-1 decreased the survival of HL cells, suggesting that Bmi-1 may mediate the prosurvival effects of LMP1-induced NF-kappaB signaling in HL cells. Transcriptional targets of Bmi-1 were identified after its knockdown in an HL cell line. We show here that Bmi-1 and LMP1 down-regulate the ataxia telangiectasia-mutated (ATM) tumor suppressor and conclude that Bmi-1 contributes to LMP1-induced oncogenesis in HL.
Assuntos
Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/metabolismo , Doença de Hodgkin/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Proteínas da Matriz Viral/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Sobrevivência Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Perfilação da Expressão Gênica , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1 , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Proteínas da Matriz Viral/genéticaRESUMO
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder resulting from mutations in the NBS1 gene, which encodes for the DNA double strand break repair protein nibrin. NBS is clinically characterized by microcephaly, dysmorphic features, immunodeficiency, and increased susceptibility to malignancy, mainly of lymphoid origin. Here, we describe a 7-year-old girl with NBS who is homozygous for the NBS1 698del4 mutation. She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is extremely uncommon but has been previously described in two cases with NBS. The strong association of perianal RMS with NBS should, therefore, be considered when confronted with a perianal RMS, as this carries important clinical implications in terms of potential need for therapy modification and follow up investigations. In addition, it suggests a role for the NBS1 gene and the nibrin dependent pathway in the pathogenesis of RMS, especially those arising perianally.
Assuntos
Anormalidades Múltiplas/diagnóstico , Microcefalia/diagnóstico , Rabdomiossarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Anormalidades Múltiplas/genética , Neoplasias do Ânus/diagnóstico , Sequência de Bases , Proteínas de Ciclo Celular/genética , Criança , Quebra Cromossômica , Fácies , Feminino , Transtornos do Crescimento/diagnóstico , Humanos , Cariotipagem , Microcefalia/genética , Proteínas Nucleares/genética , Deleção de Sequência , SíndromeRESUMO
Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder that arises because of mutations in the ATM gene. The 5762ins137 A-->G point mutation activates a cryptic splice donor site resulting in a 137 bp intronic insert being aberrantly spliced into the ATM transcript. However, normal ATM transcript also is produced from this affected allele, albeit at significantly reduced levels. An exceptionally mild A-T phenotype occurs as a result of homozygosity for the 5762ins137 mutation because of relative preservation of ATM protein expression/kinase activity.