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1.
PLoS Genet ; 12(3): e1005945, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26990772

RESUMEN

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.


Asunto(s)
Anemia de Fanconi/genética , Linfoma no Hodgkin/genética , Proteínas Nucleares/genética , Recombinasa Rad51/genética , Proteínas Supresoras de Tumor/genética , Alelos , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Cromosomas/genética , Daño del ADN/genética , Anemia de Fanconi/patología , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Humanos , Linfocitos/metabolismo , Linfocitos/patología , Linfoma no Hodgkin/patología , Mutación
2.
Croat Med J ; 56(3): 263-71, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26088851

RESUMEN

AIM: To evaluate the clinical utility of incorporating a novel heavy/light chain immunoassay (HLC) into the existing methods for the assessment of multiple myeloma (MM) patients. METHODS: Convenience sera samples from 90 previously treated IgG and IgA MM patients in different disease stages were analyzed. The study was conducted in Clinical Hospital Center Zagreb between 2011 and 2013. The collected sera were analyzed by standard laboratory techniques (serum protein electrophoresis, quantification of total immunoglobulins, serum immunofixation, serum free light chain [FLC] assay) and HLC assay. RESULTS: HLC ratios outside the normal range were found in 58 of 90 patients, including 28 out of 61 patients with total immunoglobulin measurements within the normal range and 5 out of 23 patients in complete response. Both elevated HLC isotype level and abnormal HLC ratio correlated with the parameters of tumor burden, including percentage of plasma cells in the bone marrow (P<0.001 and P=0.002, respectively) and an abnormal serum FLC ratio (for both P<0.001). In addition, abnormal HLC isotype level correlated with serum beta-2-microglobulin level (P=0.038). In terms of prognosis, abnormal HLC isotype level and abnormal HLC ratio were significantly associated with shorter overall survival (P<0.001 and P=0.002, respectively). Interestingly, suppression of the uninvolved (polyclonal) isotype pair, but not other non-myeloma immunoglobulin isotypes, was also associated with a shorter overall survival (P=0.021). In a multivariate analysis, an abnormal HLC ratio and ß2-microglobulin level >3.5mg/L were independent risk factors for survival. CONCLUSION: The new HLC assay has greater sensitivity in detecting monoclonal protein, correlates with tumor burden markers, and affects patients' outcome.


Asunto(s)
Inmunoensayo/métodos , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Ligeras de Inmunoglobulina/sangre , Cadenas Ligeras de Inmunoglobulina/inmunología , Mieloma Múltiple/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunoglobulina A , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Proteínas de Mieloma/inmunología , Pronóstico , Factores de Riesgo
3.
Growth Factors ; 32(3-4): 123-9, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25060036

RESUMEN

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.


Asunto(s)
Ataxia Telangiectasia/sangre , Estatura , Hormona de Crecimiento Humana/deficiencia , Adolescente , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/patología , Niño , Preescolar , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino
4.
Mov Disord ; 28(4): 524-8, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23143971

RESUMEN

BACKGROUND: The major clinical feature of ataxia telangiectasia (A-T) is severe progressive neurodegeneration with onset in infancy. This classical A-T phenotype is caused by biallelic null mutations in the ATM gene, leading to the absence of ATM protein and increased cellular radiosensitivity. We report an unusual case of A-T in a 41-year-old mother, A-T210, who had very mild neurological symptoms despite complete loss of ATM protein. METHODS: A neurological examination was performed, cellular radiosensitivity was assessed, and the ATM gene was sequenced. Skin fibroblasts and a lymphoblastoid cell line (LCL) were assayed for ATM protein expression and kinase activity. RESULTS: Patient A-T210 showed mild chorea, dystonia, and gait ataxia, walked independently, and drove a car. LCL and skin fibroblasts were radiosensitive and did not express ATM protein. Two ATM-null mutations were identified. CONCLUSIONS: The severe neurodegeneration resulting from loss of ATM can be mitigated in some circumstances.


Asunto(s)
Ataxia Telangiectasia/genética , Mutación/genética , Adulto , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular , Femenino , Genotipo , Humanos , Fenotipo , Tolerancia a Radiación
5.
Hum Mutat ; 33(3): 561-71, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22213089

RESUMEN

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.


Asunto(s)
Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patología , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adolescente , Adulto , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Niño , Proteínas de Unión al ADN/genética , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Adulto Joven
6.
Clin Immunol ; 140(1): 26-36, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21459046

RESUMEN

ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts.


Asunto(s)
Envejecimiento/inmunología , Ataxia Telangiectasia/inmunología , Linfocitos T CD4-Positivos/inmunología , Adulto , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Recuento de Células , Proteínas de Ciclo Celular/genética , Separación Celular , Proteínas de Unión al ADN/genética , Femenino , Citometría de Flujo , Humanos , Masculino , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética
7.
Cancer Genet Cytogenet ; 154(2): 169-74, 2004 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15474156

RESUMEN

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.


Asunto(s)
Anomalías Múltiples/diagnóstico , Microcefalia/diagnóstico , Rabdomiosarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Anomalías Múltiples/genética , Neoplasias del Ano/diagnóstico , Secuencia de Bases , Proteínas de Ciclo Celular/genética , Niño , Rotura Cromosómica , Facies , Femenino , Trastornos del Crecimiento/diagnóstico , Humanos , Cariotipificación , Microcefalia/genética , Proteínas Nucleares/genética , Eliminación de Secuencia , Síndrome
8.
J Clin Invest ; 124(7): 3137-46, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24911150

RESUMEN

Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration.


Asunto(s)
Trastornos por Deficiencias en la Reparación del ADN/genética , Proteínas Mutantes/genética , Mutación Missense , Antígeno Nuclear de Célula en Proliferación/genética , Adolescente , Adulto , Envejecimiento Prematuro/genética , Sustitución de Aminoácidos , Niño , Cromosomas Humanos Par 20/genética , Análisis Mutacional de ADN , Trastornos por Deficiencias en la Reparación del ADN/patología , Trastornos por Deficiencias en la Reparación del ADN/fisiopatología , Enanismo/genética , Femenino , Pérdida Auditiva/genética , Homocigoto , Humanos , Masculino , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Degeneración Nerviosa/genética , Linaje , Fenotipo , Trastornos por Fotosensibilidad/genética , Antígeno Nuclear de Célula en Proliferación/química , Antígeno Nuclear de Célula en Proliferación/metabolismo , Estructura Cuaternaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Síndrome , Telangiectasia/genética
9.
Neuromolecular Med ; 15(3): 447-57, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23632773

RESUMEN

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.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Ataxia Telangiectasia/genética , Adulto , Sustitución de Aminoácidos , Proteínas de la Ataxia Telangiectasia Mutada/química , Proteínas de la Ataxia Telangiectasia Mutada/fisiología , Neoplasias de la Mama/genética , Cafeína/farmacología , Niño , Exones/genética , Femenino , Fase G2 , Heterocigoto , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/efectos de la radiación , Masculino , Pruebas de Micronúcleos , Mutación Missense , Síndromes Neoplásicos Hereditarios/genética , Examen Neurológico , Linaje , Fenotipo , Sitios de Empalme de ARN/genética , Tolerancia a Radiación/genética , Reparación del ADN por Recombinación/genética , Rabdomiosarcoma Embrionario/genética , Fase S , Análisis de Secuencia de ADN
10.
Blood ; 109(6): 2597-603, 2007 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-17148591

RESUMEN

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.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4/metabolismo , Enfermedad de Hodgkin/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Proteínas de la Matriz Viral/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Supervivencia Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Perfilación de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Complejo Represivo Polycomb 1 , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba , Proteínas de la Matriz Viral/genética
11.
J Natl Cancer Inst ; 97(11): 813-22, 2005 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-15928302

RESUMEN

BACKGROUND: Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain. METHODS: Cancer incidence and mortality information for 1160 relatives of 169 UK A-T patients (including 247 obligate carriers) was obtained through the National Health Service Central Registry. Relative risks (RRs) of cancer in carriers, allowing for genotype uncertainty, were estimated with a maximum-likelihood approach that used the EM algorithm. Maximum-likelihood estimates of cancer risks associated with three groups of mutations were calculated using the pedigree analysis program MENDEL. All statistical tests were two-sided. RESULTS: The overall relative risk of breast cancer in carriers was 2.23 (95% confidence interval [CI] = 1.16 to 4.28) compared with the general population but was 4.94 (95% CI = 1.90 to 12.9) in those younger than age 50 years. The relative risk for all cancers other than breast cancer was 2.05 (95% CI = 1.09 to 3.84) in female carriers and 1.23 (95% CI = 0.76 to 2.00) in male carriers. Breast cancer was the only site for which a clear risk increase was seen, although there was some evidence of excess risks of colorectal cancer (RR = 2.54, 95% CI = 1.06 to 6.09) and stomach cancer (RR = 3.39, 95% CI = 0.86 to 13.4). Carriers of mutations predicted to encode a full-length ATM protein had cancer risks similar to those of people carrying truncating mutations. CONCLUSION: These results confirm a moderate risk of breast cancer in A-T heterozygotes and give some evidence of an excess risk of other cancers but provide no support for large mutation-specific differences in risk.


Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Mutación , Neoplasias/epidemiología , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Algoritmos , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Intervalos de Confianza , Femenino , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Linaje , Fenotipo , Medición de Riesgo , Factores de Riesgo , Reino Unido/epidemiología
12.
Blood ; 99(1): 300-9, 2002 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-11756185

RESUMEN

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease involving more than one molecular mechanism that leads to the transformation of CD5(+) B cells at either the pregerminal or postgerminal center stage of differentiation. It was previously demonstrated that ataxia telangiectasia mutated (ATM) gene mutations can occur in B-CLL and cause a defect in the p53 pathway. Here the role of ATM mutations in the pathogenesis of B-CLL is addressed. Of 50 B-CLL tumors with fully analyzed ATM and TP53, 16 had ATM mutations. Six of 50 B-CLLs showed mutations in TP53 and the remaining 28 tumors had wild-type ATM or TP53. No tumor had both ATM and TP53 mutations. Remarkably, all 16 ATM mutant B-CLLs showed the absence of somatic variable region heavy chain hypermutation indicating a pregerminal center cell origin and a common pathogenesis for these tumors. Furthermore, in 5 of the 16 B-CLLs, ATM mutation preceded the transformation stage of differentiation. At the cellular level, ATM mutant tumors exhibited a deficient ATM-dependent p53 response to gamma irradiation, failure to up-regulate TRAIL-R2, a downstream target that links irradiation-induced p53 response with apoptosis, and an inability to repair induced chromosome breaks. Mantle cell lymphoma (MCL) is also of pregerminal center origin and ATM mutations are frequent in this malignancy. It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.


Asunto(s)
Daño del ADN , Reparación del ADN/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de la radiación , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Femenino , Rayos gamma , Expresión Génica , Genes p53/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Masculino , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/análisis , Proteínas Serina-Treonina Quinasas/deficiencia , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor
13.
Ann Neurol ; 55(6): 891-5, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15174027

RESUMEN

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.


Asunto(s)
Ataxia Telangiectasia/genética , Homocigoto , Mutación Puntual , Proteínas Serina-Treonina Quinasas/genética , Adulto , Alanina/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patología , Proteínas de la Ataxia Telangiectasia Mutada , Células Sanguíneas/metabolismo , Células Sanguíneas/efectos de la radiación , Western Blotting/métodos , Proteínas de Ciclo Celular , Línea Celular , Cerebelo/patología , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Glicina/genética , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Sitios de Empalme de ARN , Tolerancia a Radiación/genética , Serina , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor
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