17 results on '"Last JI"'
Search Results
2. Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.
- Author
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Hiel JAP, van Engelen BGM, Weemaes CMR, Broeks A, Verrips A, ter Laak H, Vingerhoets HM, van den Heuvel LPW, Lammens M, Gabreëls FJM, Last JI, and Taylor AMR
- Published
- 2006
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3. A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.
- Author
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Byrd PJ, Stewart GS, Smith A, Eaton C, Taylor AJ, Guy C, Eringyte I, Fooks P, Last JI, Horsley R, Oliver AW, Janic D, Dokmanovic L, Stankovic T, and Taylor AM
- Subjects
- Alleles, BRCA2 Protein genetics, BRCA2 Protein metabolism, Chromosomes genetics, DNA Damage genetics, Fanconi Anemia pathology, Fanconi Anemia Complementation Group N Protein, Humans, Lymphocytes metabolism, Lymphocytes pathology, Lymphoma, Non-Hodgkin pathology, Mutation, Fanconi Anemia genetics, Lymphoma, Non-Hodgkin genetics, Nuclear Proteins genetics, Rad51 Recombinase genetics, Tumor Suppressor Proteins genetics
- Abstract
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.
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- 2016
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4. Ataxia telangiectasia: more variation at clinical and cellular levels.
- Author
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Taylor AM, Lam Z, Last JI, and Byrd PJ
- Subjects
- Age of Onset, Ataxia Telangiectasia complications, Ataxia Telangiectasia epidemiology, Ataxia Telangiectasia genetics, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia Mutated Proteins deficiency, Ataxia Telangiectasia Mutated Proteins genetics, DNA-Binding Proteins genetics, Disease Progression, Enzyme Activation, Genetic Heterogeneity, Humans, MRE11 Homologue Protein, Mutation, Neoplasms etiology, Phenotype, Signal Transduction, Ubiquitin-Protein Ligases genetics, Ataxia Telangiectasia diagnosis
- Abstract
Ataxia telangiectasia (A-T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by auto(trans)phosphorylation in response to DNA double strand breaks and leads to the activation of cell cycle checkpoints and either DNA repair or apoptosis as part of the cellular response to DNA damage. The allelic heterogeneity in A-T is striking. While the majority of mutations are truncating, leading to instability and loss of the ATM protein from the allele, a significant proportion of patients carry one of a small number of mutations that are either missense or leaky splice site mutations resulting in retention of some ATM with activity. The allelic heterogeneity in ATM, therefore, results in an equally striking clinical heterogeneity. There is also locus heterogeneity because mutation of the MRE11 gene can cause an obvious A-T like disorder both clinically and also at the cellular level and mutation of the RNF168 gene results in a much milder clinical phenotype, neurologically, with the major clinical feature being an immunological defect., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
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5. Hypomorphic PCNA mutation underlies a human DNA repair disorder.
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Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, and Crosby AH
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- Adolescent, Adult, Aging, Premature genetics, Amino Acid Substitution, Child, Chromosomes, Human, Pair 20 genetics, DNA Mutational Analysis, DNA Repair-Deficiency Disorders pathology, DNA Repair-Deficiency Disorders physiopathology, Dwarfism genetics, Female, Hearing Loss genetics, Homozygote, Humans, Male, Models, Molecular, Mutant Proteins chemistry, Mutant Proteins metabolism, Nerve Degeneration genetics, Pedigree, Phenotype, Photosensitivity Disorders genetics, Proliferating Cell Nuclear Antigen chemistry, Proliferating Cell Nuclear Antigen metabolism, Protein Structure, Quaternary, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Syndrome, Telangiectasis genetics, DNA Repair-Deficiency Disorders genetics, Mutant Proteins genetics, Mutation, Missense, Proliferating Cell Nuclear Antigen genetics
- Abstract
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.
- Published
- 2014
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6. Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia.
- Author
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Voss S, Pietzner J, Hoche F, Taylor AM, Last JI, Schubert R, and Zielen S
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- Adolescent, Ataxia Telangiectasia diagnosis, Ataxia Telangiectasia pathology, Child, Child, Preschool, Female, Human Growth Hormone blood, Humans, Insulin-Like Growth Factor Binding Protein 3 blood, Insulin-Like Growth Factor I metabolism, Male, Ataxia Telangiectasia blood, Body Height, Human Growth Hormone deficiency
- Abstract
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.
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- 2014
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7. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives.
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Claes K, Depuydt J, Taylor AM, Last JI, Baert A, Schietecatte P, Vandersickel V, Poppe B, De Leeneer K, D'Hooghe M, and Vral A
- Subjects
- Adult, Amino Acid Substitution, Ataxia Telangiectasia Mutated Proteins chemistry, Ataxia Telangiectasia Mutated Proteins physiology, Breast Neoplasms genetics, Caffeine pharmacology, Child, Exons genetics, Female, G2 Phase, Heterozygote, Humans, Lymphocytes drug effects, Lymphocytes radiation effects, Male, Micronucleus Tests, Mutation, Missense, Neoplastic Syndromes, Hereditary genetics, Neurologic Examination, Pedigree, Phenotype, RNA Splice Sites genetics, Radiation Tolerance genetics, Recombinational DNA Repair genetics, Rhabdomyosarcoma, Embryonal genetics, S Phase, Sequence Analysis, DNA, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins genetics
- Abstract
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.
- Published
- 2013
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8. Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia.
- Author
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Worth PF, Srinivasan V, Smith A, Last JI, Wootton LL, Biggs PM, Davies NP, Carney EF, Byrd PJ, and Taylor AM
- Subjects
- Adult, Ataxia Telangiectasia diagnosis, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia Mutated Proteins metabolism, Cell Line, Female, Genotype, Humans, Phenotype, Radiation Tolerance, Ataxia Telangiectasia genetics, Mutation genetics
- Abstract
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., (Copyright © 2012 Movement Disorders Society.)
- Published
- 2013
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9. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
- Author
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Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, Brunt ER, Peeters EA, Gómez Garcia EB, van der Knaap MS, Lincke CR, Laan LA, Tijssen MA, van Rijn MA, Majoor-Krakauer D, Visser M, van 't Veer LJ, Kleijer WJ, van de Warrenburg BP, Warris A, de Groot IJ, de Groot R, Broeks A, Preijers F, Kremer BH, Weemaes CM, Taylor MA, van Deuren M, and Willemsen MA
- Subjects
- Adolescent, Adult, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Child, DNA-Binding Proteins genetics, Female, Genetic Association Studies, Humans, Male, Middle Aged, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins genetics, Young Adult, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia pathology, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins metabolism
- Abstract
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., (© 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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10. Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia.
- Author
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Byrd PJ, Srinivasan V, Last JI, Smith A, Biggs P, Carney EF, Exley A, Abson C, Stewart GS, Izatt L, and Taylor AM
- Subjects
- Ataxia Telangiectasia complications, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms complications, Breast Neoplasms genetics, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Female, Humans, Middle Aged, Mutation, Protein Serine-Threonine Kinases genetics, Radiation Tolerance, Tumor Suppressor Proteins genetics, Ataxia Telangiectasia diagnosis, Breast Neoplasms radiotherapy
- Abstract
Background: Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213)., Methods: A neurological examination was performed and blood lymphocytes and skin fibroblasts were assessed for radiosensitivity chromosomally and by colony-forming assay. The ATM gene was sequenced and ATM mutations modelled by site-directed mutagenesis. The ATM kinase activity was also assessed., Results: Patient A-T213 was normally ambulant with no ataxia and minimal other neurological features. T lymphocytes and skin fibroblasts were unusually radiosensitive, although less sensitive than in classical ataxia telangiectasia (A-T). A lymphoblastoid cell line and skin fibroblasts expressed ATM protein with some retained kinase activity. One missense ATM mutation c.8672G>A (p.Gly2891Asp) and a c.1A>G substitution were identified. In the modelling system, the p.Gly2891Asp mutant protein was expressed and shown to have residual ATM kinase activity., Conclusion: Patient A-T213 has a milder form of A-T with biallelic ATM mutations, which may have contributed to breast cancer development, and certainly caused the severe radiation reaction. Ataxia telangiectasia should be investigated as a potential cause of untoward severe early and late radiation reactions in breast cancer patients.
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- 2012
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11. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.
- Author
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Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL, Davies EG, Verhagen MM, Willemsen MA, Weemaes CM, Byrd PJ, Izatt L, Easton DF, Thompson DJ, and Taylor AM
- Subjects
- Adolescent, Adult, Ataxia Telangiectasia enzymology, Ataxia Telangiectasia Mutated Proteins, Brain Neoplasms enzymology, Brain Neoplasms prevention & control, Breast Neoplasms enzymology, Breast Neoplasms prevention & control, Child, Female, Humans, Immunoblotting, Kaplan-Meier Estimate, Lymphoma enzymology, Lymphoma prevention & control, Male, Netherlands, Protein Serine-Threonine Kinases genetics, United Kingdom, Young Adult, Ataxia Telangiectasia genetics, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Mutation, Neoplasms enzymology, Neoplasms prevention & control, Protein Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins genetics
- Abstract
Background: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T., Methods: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity., Results: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype., Conclusion: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.
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- 2011
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12. Bmi-1 is induced by the Epstein-Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells.
- Author
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Dutton A, Woodman CB, Chukwuma MB, Last JI, Wei W, Vockerodt M, Baumforth KR, Flavell JR, Rowe M, Taylor AM, Young LS, and Murray PG
- Subjects
- Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Cell Survival, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Down-Regulation, Gene Expression Profiling, Hodgkin Disease genetics, Hodgkin Disease pathology, Humans, NF-kappa B metabolism, Nuclear Proteins genetics, Polycomb Repressive Complex 1, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Up-Regulation, Viral Matrix Proteins genetics, Gene Expression Regulation, Neoplastic, Herpesvirus 4, Human metabolism, Hodgkin Disease metabolism, Nuclear Proteins metabolism, Proto-Oncogene Proteins metabolism, Repressor Proteins metabolism, Viral Matrix Proteins metabolism
- Abstract
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.
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- 2007
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13. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site.
- Author
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Meyer S, Kingston H, Taylor AM, Byrd PJ, Last JI, Brennan BM, Trueman S, Kelsey A, Taylor GM, and Eden OB
- Subjects
- Abnormalities, Multiple genetics, Anus Neoplasms diagnosis, Base Sequence, Cell Cycle Proteins genetics, Child, Chromosome Breakage, Facies, Female, Growth Disorders diagnosis, Humans, Karyotyping, Microcephaly genetics, Nuclear Proteins genetics, Sequence Deletion, Syndrome, Abnormalities, Multiple diagnosis, Microcephaly diagnosis, Rhabdomyosarcoma diagnosis, Soft Tissue Neoplasms diagnosis
- Abstract
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.
- Published
- 2004
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14. Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity.
- Author
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Sutton IJ, Last JI, Ritchie SJ, Harrington HJ, Byrd PJ, and Taylor AM
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- Adult, Alanine genetics, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia pathology, Ataxia Telangiectasia Mutated Proteins, Blood Cells metabolism, Blood Cells radiation effects, Blotting, Western methods, Cell Cycle Proteins, Cell Line, Cerebellum pathology, DNA Mutational Analysis, DNA-Binding Proteins, Glycine genetics, Humans, Magnetic Resonance Imaging methods, Male, Phosphorylation, Protein Serine-Threonine Kinases metabolism, RNA Splice Sites, Radiation Tolerance genetics, Serine, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins, Ataxia Telangiectasia genetics, Homozygote, Point Mutation, Protein Serine-Threonine Kinases genetics
- Abstract
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.
- Published
- 2004
- Full Text
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15. A late onset variant of ataxia-telangiectasia with a compound heterozygous genotype, A8030G/7481insA.
- Author
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Saviozzi S, Saluto A, Taylor AM, Last JI, Trebini F, Paradiso MC, Grosso E, Funaro A, Ponzio G, Migone N, and Brusco A
- Subjects
- Adult, Female, Genotype, Humans, Male, Middle Aged, Pedigree, Adenine, Ataxia Telangiectasia genetics, Genetic Carrier Screening, Guanine, Mutagenesis, Insertional genetics, Point Mutation genetics
- Published
- 2002
- Full Text
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16. Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype.
- Author
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Stewart GS, Last JI, Stankovic T, Haites N, Kidd AM, Byrd PJ, and Taylor AM
- Subjects
- Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, Cells, Cultured, DNA Damage, DNA Repair, DNA-Binding Proteins, Enzyme Activation, Gene Deletion, Heterozygote, Homozygote, Humans, Immunoblotting, JNK Mitogen-Activated Protein Kinases, Kinetics, Mitogen-Activated Protein Kinases metabolism, Mutation, Phenotype, Phosphorylation, Precipitin Tests, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2, Proto-Oncogene Proteins p21(ras) metabolism, Radiation, Ionizing, Serine metabolism, Time Factors, Transcriptional Activation, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins, Ataxia Telangiectasia genetics, Nuclear Proteins, Point Mutation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology
- Abstract
We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T-->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T-->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T-->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T-->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or c-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.
- Published
- 2001
- Full Text
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17. hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay.
- Author
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Pitts SA, Kullar HS, Stankovic T, Stewart GS, Last JI, Bedenham T, Armstrong SJ, Piane M, Chessa L, Taylor AM, and Byrd PJ
- Subjects
- Alleles, Ataxia Telangiectasia metabolism, Base Sequence, Cell Line, DNA Mutational Analysis, DNA-Binding Proteins metabolism, Exons, Genetic Vectors, Humans, MRE11 Homologue Protein, Molecular Sequence Data, Protein Biosynthesis, Pseudogenes, Ataxia Telangiectasia genetics, DNA-Binding Proteins genetics, Genome, Mutation, Promoter Regions, Genetic, RNA, Messenger genetics
- Abstract
We showed recently that mutation of the hMRE11 gene identified a new ataxia telangiectasia-like disorder (ATLD). In this report we describe the genomic organization of the hMRE11 gene and the analysis of a promoter region that appears to direct the divergent transcription of hMRE11 and the adjacent gene. The characterization of the genomic organization of the hMRE11 gene allowed us to determine the basis of an apparent null hMRE11 allele present in the mother and two patients in one of our two ATLD families. Polymorphic markers in the hMRE11 gene, including the promoter region, provided evidence that the mutated maternal allele was not deleted. An exon by exon search revealed the presence of a missense mutation in exon 15, the effect of which was to create a premature termination codon. Transcripts derived from the mutant allele were found to be subject to nonsense-mediated mRNA decay (NMD). Therefore, this allele was effectively null, because little if any mRNA from it was available for translation. The ATLD patients carrying this protein-truncating hMRE11 mutation have survived because the null allele they inherited from their mother is present with a missense mutation inherited from their father, which is expressed as normal levels of partially functional MRE11 protein. The mutation in the maternal hMRE11 allele of family 2 was also identified in a further unrelated Italian family with ATLD and also found to be subject to NMD.
- Published
- 2001
- Full Text
- View/download PDF
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