ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele.

الزيارات: 523

2012 Jan;97(1):142-6. doi: 10.3324/haematol.2011.048827. Epub 2011 Sep 20.

Skowronska A¹, Austen B, Powell JE, Weston V, Oscier DG, Dyer MJ, Matutes E, Pratt G, Fegan C, Moss P, Taylor MA, Stankovic T.

Author information

1: School of Cancer Sciences, University of Birmingham, University of Birmingham, Birmingham B15 2TT, UK. t.stankovic@bham.ac.uk

Abstract

Ataxia telangiectasia patients, with constitutional bi-allelic ATM mutations, have a marked risk of lymphoid tumors and ATM mutation carriers have a smaller risk of cancer. Sporadic ATM mutations occur in 10-20% of chronic lymphocytic leukemia and are often associated with chromosome 11q deletions which cause loss of an ATM allele. The role of constitutional ATM mutations in the pathogenesis of chronic lymphocytic leukemia is unknown. Here we investigated the frequency of constitutional ATM mutations in either of two chronic lymphocytic leukemia cohorts, those with and without a chromosome 11q deletion. We found that in comparison to controls, constitutional pathogenic ATM mutations were increased in patients with chromosome 11q deletions (6 of 140 vs. 0 of 281, P = 0.001) but not in those without 11q deletions (2 of 178 vs. 0 of 281, P = 0.15). These results suggest that ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but rather influences rapid disease progression through ATM loss.

Comment in

ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter. [Haematologica. 2012]

PMID:: 21933854
PMCID:: PMC3248944
DOI:: 10.3324/haematol.2011.048827

[Indexed for MEDLINE]

Free PMC Article

A germline chromothripsis event stably segregating in 11 individuals through three generations.

الزيارات: 555

2016 May;18(5):494-500. doi: 10.1038/gim.2015.112. Epub 2015 Aug 27.

Bertelsen B¹, Nazaryan-Petersen L¹, Sun W², Mehrjouy MM³, Xie G², Chen W², Hjermind LE⁴, Taschner PE⁵, Tümer Z¹.

Author information

1: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
2: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
3: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
4: Neurogenetics Clinic, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, and Department of Cellular and Molecular Medicine, Section of Neurogenetics, University of Copenhagen, Copenhagen, Denmark.
5: Generade Center of Expertise Genomics; University of Applied Sciences Leiden, Leiden, The Netherlands.

Abstract

PURPOSE:

Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers.

METHODS:

Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations.

RESULTS:

We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia-telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation.

CONCLUSION:

G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.Genet Med 18 5, 494-500.

PMID:: 26312826
DOI:: 10.1038/gim.2015.112

[Indexed for MEDLINE]

Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination.

الزيارات: 560

2016 Apr;37(4):385-95. doi: 10.1002/humu.22953. Epub 2016 Feb 4.

Nazaryan-Petersen L^1,², Bertelsen B¹, Bak M³, Jønson L⁴, Tommerup N³, Hancks DC⁵, Tümer Z¹.

Author information

1: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, 2600, Denmark.
2: Department of Cellular and Molecular Medicine (ICMM), Faculty of Health Science, University of Copenhagen, Copenhagen, N. 2200, Denmark.
3: Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, N. 2200, Denmark.
4: Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, O. 2100, Denmark.
5: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, 84112.

Abstract

Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.

KEYWORDS:

Alu; L1; LINE-1; NAHR; SINE-VNTR-Alu; SVA; chromothripsis; nonallelic homologous recombination

Comment in

A Mechanistic Link between L1 Retrotransposition and Chromothripsis. [Hum Mutat. 2016]

PMID:: 26929209
DOI:: 10.1002/humu.22953

[Indexed for MEDLINE]

Non invasive assessment of lung disease in ataxia telangiectasia by high-field magnetic resonance imaging.

الزيارات: 518

2013 Oct;33(7):1185-91. doi: 10.1007/s10875-013-9933-y. Epub 2013 Aug 24.

Montella S¹, Mollica C, Finocchi A, Pession A, Pietrogrande MC, Trizzino A, Ranucci G, Maglione M, Giardino G, Salvatore M, Santamaria F, Pignata C.

Author information

1: Department of Translational Medical Sciences, "Federico II" University, Via Pansini 5, 80131, Naples, Italy.

Abstract

PURPOSE:

A sensitive imaging technique that assesses ataxia telangiectasia (AT) lung disease without ionizing radiation is highly desirable. We designed a study to evaluate lung changes using magnetic resonance imaging (MRI), and to investigate the relationships among severity and extent of pulmonary abnormalities and clinical, microbiological and functional data in children and young adults with AT.

METHODS:

Fifteen AT patients (age, 11.3 years; range, 6-31) underwent 3.0-T MRI, spirometry, and deep throat or sputum culture. Images were scored using a modified Helbich score.

RESULTS:

Although only 8 patients (53 %) had recurrent/chronic respiratory symptoms, MRI identified lung abnormalities in all. Bronchiectasis, peribronchial thickening, mucous plugging, and collapse/consolidation were present in 60 %, 87 %, 67 %, and 13 % of cases, respectively, with no difference between subjects with or without respiratory symptoms. No difference in changes of specific scores was found between the two groups, but the total MRI score was higher in patients with respiratory symptoms (6.5 versus 5, respectively; p = 0.02). Total or specific MRI scores were not associated with patients' age. Of all scores, only mucous plugging subscore appeared significantly related to FEV1 (r = 0.7, p = 0.04) and FEF25-75% (r = 0.9, p = 0.001). MRI scores from patients with positive (n = 5) or negative (n = 10) sputum culture were not significantly different.

CONCLUSIONS:

MRI is valuable in the assessment of extent and severity of pulmonary changes in children and adults with AT. It represents an helpful tool for the longitudinal evaluation of patients and may be also used as an outcome surrogate to track the effects of medications.

PMID:: 23975689
DOI:: 10.1007/s10875-013-9933-y

[Indexed for MEDLINE]

Senataxin controls meiotic silencing through ATR activation and chromatin remodeling.

الزيارات: 562

2015 Sep 29;1:15025. doi: 10.1038/celldisc.2015.25. eCollection 2015.

controls meiotic silencing through ATR activation and chromatin remodeling.

Yeo AJ¹, Becherel OJ², Luff JE³, Graham ME⁴, Richard D⁵, Lavin MF¹.

Author information

1: The University of Queensland, UQ Centre for Clinical Research (UQCCR), Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Herston, Brisbane, QLD, Australia.
2: The University of Queensland, UQ Centre for Clinical Research (UQCCR), Brisbane, QLD, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia.
3: The University of Queensland, UQ Centre for Clinical Research (UQCCR) , Brisbane, QLD, Australia.
4: Children's Medical Research Institute, The University of Sydney , Westmead, NSW, Australia.
5: Cancer and Ageing Research Program, Faculty of Health, Queensland University of Technology , Brisbane, QLD, Australia.

Abstract

Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA-DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx (-/-) pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration.

KEYWORDS:

DNA damage repair; chromatin remodeling; meiosis; senataxin; transcription

PMID:: 27462424
PMCID:: PMC4860845
DOI:: 10.1038/celldisc.2015.25

Free PMC Article

Cerebral abnormalities in adults with ataxia-telangiectasia.

الزيارات: 514

2014 Jan;35(1):119-23. doi: 10.3174/ajnr.A3646. Epub 2013 Jul 25.

Cerebral abnormalities in adults with ataxia-telangiectasia.

Lin DD¹, Barker PB, Lederman HM, Crawford TO.

Author information

1: Departments of Radiology and Radiological Science.

Abstract

Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiectasia having stable neurologic impairment. Intracerebral telangiectasia with multiple punctate hemosiderin deposits were identified in 60% of subjects. These lesions were apparently asymptomatic. They are similar in appearance to radiation-induced telangiectasia and to cryptogenic vascular malformations. Also noted, in the 2 oldest subjects, was extensive white matter T2 hyperintensity, and in 1 of these a space-occupying fluid collection consistent with transudative capillary leak and edema as evidenced by reduced levels of metabolites on MR spectroscopic imaging. Asymptomatic supratentorial vascular abnormalities appear to be common in adults with ataxia-telangiectasia.

PMID:: 23886747
PMCID:: PMC4106125
DOI:: 10.3174/ajnr.A3646

[Indexed for MEDLINE]

Free PMC Article

Disorders of Upper Limb Movements in Ataxia-Telangiectasia.

الزيارات: 619

2013 Jun 27;8(6):e67042. doi: 10.1371/journal.pone.0067042. Print 2013.

Shaikh AG¹, Zee DS, Mandir AS, Lederman HM, Crawford TO.

Author information

1: Department of Neurology, Case Western Reserve University, Cleveland, Ohio, United States of America.

Abstract

Ataxia-telangiectasia is known for cerebellar degeneration, but clinical descriptions of abnormal tone, posture, and movements suggest involvement of the network between cerebellum and basal ganglia. We quantitatively assessed the nature of upper-limb movement disorders in ataxia-telangiectasia. We used a three-axis accelerometer to assess the natural history and severity of abnormal upper-limb movements in 80 ataxia-telangiectasia and 19 healthy subjects. Recordings were made during goal-directed movements of upper limb (kinetic task), while arms were outstretched (postural task), and at rest. Almost all ataxia-telangiectasia subjects (79/80) had abnormal involuntary movements, such as rhythmic oscillations (tremor), slow drifts (dystonia or athetosis), and isolated rapid movements (dystonic jerks or myoclonus). All patients with involuntary movements had both kinetic and postural tremor, while 48 (61%) also had resting tremor. The tremor was present in transient episodes lasting several seconds during two-minute recording sessions of all three conditions. Percent time during which episodic tremor was present was greater for postural and kinetic tasks compared to rest. Resting tremor had higher frequency but smaller amplitude than postural and kinetic tremor. Rapid non-rhythmic movements were minimal during rest, but were triggered during sustained arm postures and goal directed arm movements suggesting they are best considered a form of dystonic jerks or action myoclonus. Advancing age did not correlate with the severity of involuntary limb movements. Abnormal upper-limb movements in ataxia-telangiectasia feature classic cerebellar impairment, but also suggest involvement of the network between the cerebellum and basal ganglia.

PMID:: 23826191
PMCID:: PMC3694953
DOI:: 10.1371/journal.pone.0067042

[Indexed for MEDLINE]

Free PMC Article

Pulmonary function in children and young adults with ataxia telangiectasia.

الزيارات: 587

2014 Jan;49(1):84-90. doi: 10.1002/ppul.22760. Epub 2013 Feb 8.

McGrath-Morrow SA¹, Lederman HM, Aherrera AD, Lefton-Greif MA, Crawford TO, Ryan T, Wright J, Collaco JM.

Author information

1: Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Abstract

BACKGROUND:

Pulmonary disease contributes to significant morbidity and mortality in people with ataxia telangiectasia (A-T). To determine the association between age and lung function in children and young adults with A-T and to identify factors associated with decreased lung function, pulmonary function tests were performed in 100 consecutive people with A-T.

METHODS:

Children and adults ranging from 6 to 29 years of age and with the diagnosis of A-T were recruited, and underwent pulmonary function tests.

RESULTS:

The mean forced vital capacity % predicted (FVC %) in the population was 56.6 ± 20.0. Males and females between 6 and 10 years of age had similar pulmonary function. Older females were found to have significantly lower FVCs % than both older males (P < 0.02) and younger females (P < 0.001). The use of supplemental gamma globulin was associated with significantly lower FVC %. A modest correlation was found between higher radiation-induced chromosomal breakage and lower FVC % in males. No significant change in FVC % was found in a subset of subjects (n = 25) who underwent pulmonary function testing on two or more occasions over an average of 2 years.

CONCLUSION:

In children and young adults with A-T, older females and people who required supplemental gamma globulin had significantly lower lung function by cross-sectional analysis. Stable lung function is possible over a 2-year period. Recognition of groups who are at higher risk for lower pulmonary function may help direct care and improve clinical outcomes in people with A-T.

KEYWORDS:

ataxia telangiectasia; lung; pulmonary function

PMID:: 23401357
PMCID:: PMC4423797
DOI:: 10.1002/ppul.22760

[Indexed for MEDLINE]

Free PMC Article

Anesthetic and perioperative risk in the patient with Ataxia-Telangiectasia.

الزيارات: 608

2012 Mar;22(3):256-62. doi: 10.1111/j.1460-9592.2011.03739.x. Epub 2011 Nov 21.

Lockman JL¹, Iskander AJ, Bembea M, Crawford TO, Lederman HM, McGrath-Morrow S, Easley RB.

Author information

1: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA.

Abstract

OBJECTIVES/AIM:

To report our relatively large experience with perioperative care for patients with Ataxia-Telangiectasia (A-T) and to identify the nature and frequency of complications.

BACKGROUND:

Ataxia-Telangiectasia is a rare autosomal recessive genetic disorder resulting in progressive multisystem degeneration and characteristic findings including complex neurodegeneration, immunodeficiency, increased risk of malignancy, and lung disease. Anecdotal reports have suggested high perioperative morbidity in patients with A-T, but few data exist.

METHODS/MATERIALS:

The Ataxia-Telangiectasia Clinical Center database was cross-referenced with operative records between 1995 and 2009 to identify patients with perioperative A-T, and medical records were reviewed for preoperative history, management techniques, and complications.

RESULTS:

Twenty-one patients with A-T underwent 34 anesthetics during the study period. The median age was 12.5 years (range 6-33 years). Common comorbidities included neurologic (100%), pulmonary (68%), immunologic (50%), oncologic (47%), and gastroenterologic (35%) disorders. Supplemental oxygen was required on postanesthesia care unit discharge for 24% of patients with a maximal duration of 24 h. Although mild postoperative hypothermia was relatively common (44% of anesthetics), there were no major complications, no unplanned admissions, and no mortality in this series.

CONCLUSIONS:

Although limited by its retrospective nature, this is the first series describing perioperative risk for patients with A-T. Our results indicate that general anesthesia, airway manipulation, and perioperative mechanical ventilation may be tolerated with only minor postoperative anesthetic concerns. Perioperative providers should be aware of the complex multisystem medical concerns that may arise in these patients.

PMID:: 22098343
DOI:: 10.1111/j.1460-9592.2011.03739.x

[Indexed for MEDLINE]

Proteomic Characterization of Cerebrospinal Fluid from Ataxia-Telangiectasia (A-T) Patients Using a LC/MS-Based Label-Free Protein Quantification Technology.

الزيارات: 540

2011;2011:578903. doi: 10.1155/2011/578903. Epub 2011 Jun 23.

Dzieciatkowska M¹, Qi G, You J, Bemis KG, Sahm H, Lederman HM, Crawford TO, Gelbert LM, Rothblum-Oviatt C, Wang M.

Author information

1: Department Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 4053, Indianapolis, IN 46202, USA.

Abstract

Cerebrospinal fluid (CSF) has been used for biomarker discovery of neurodegenerative diseases in humans since biological changes in the brain can be seen in this biofluid. Inactivation of A-T-mutated protein (ATM), a multifunctional protein kinase, is responsible for A-T, yet biochemical studies have not succeeded in conclusively identifying the molecular mechanism(s) underlying the neurodegeneration seen in A-T patients or the proteins that can be used as biomarkers for neurologic assessment of A-T or as potential therapeutic targets. In this study, we applied a high-throughput LC/MS-based label-free protein quantification technology to quantitatively characterize the proteins in CSF samples in order to identify differentially expressed proteins that can serve as potential biomarker candidates for A-T. Among 204 identified CSF proteins with high peptide-identification confidence, thirteen showed significant protein expression changes. Bioinformatic analysis revealed that these 13 proteins are either involved in neurodegenerative disorders or cancer. Future molecular and functional characterization of these proteins would provide more insights into the potential therapeutic targets for the treatment of A-T and the biomarkers that can be used to monitor or predict A-T disease progression. Clinical validation studies are required before any of these proteins can be developed into clinically useful biomarkers.

PMID:: 22084690
PMCID:: PMC3200215
DOI:: 10.1155/2011/578903

Free PMC Article

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controls meiotic silencing through ATR activation and chromatin remodeling.

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Cerebral abnormalities in adults with ataxia-telangiectasia.

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