384 results on '"Hoeijmakers JH"'
Search Results
2. Transcriptional profiling reveals progeroid Ercc1-/\u0394 mice as a model system for glomerular aging
- Author
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Schermer B, Bartels V, Frommolt P, Habermann B, Braun F, Schultze JL, Roodbergen M, Hoeijmakers JH, Schumacher B, Nxfcrnberg P, Dollxe9 ME, Benzing T, Mxfcller RU, and Kurschat CE
- Published
- 2013
3. Nucleotide Excision Repair
- Author
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Hoeijmakers, JH, primary
- Published
- 2015
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4. Refining analyses of copy number variation identifies specific genes associated with developmental delay
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Coe, BP, Witherspoon, K, Rosenfeld, JA, van Bon, BWM, Vulto-van Silfhout, AT, Bosco, P, Friend, KL, Baker, C, Buono, S, Vissers, LELM, Schuurs-Hoeijmakers, JH, Hoischen, A, Pfundt, R, Krumm, N, Carvill, GL, Li, D, Amaral, D, Brown, N, Lockhart, PJ, Scheffer, IE, Alberti, A, Shaw, M, Pettinato, R, Tervo, R, de Leeuw, N, Reijnders, MRF, Torchia, BS, Peeters, H, O'Roak, BJ, Fichera, M, Hehir-Kwa, JY, Shendure, J, Mefford, HC, Haan, E, Gecz, J, de Vries, BBA, Romano, C, Eichler, EE, Coe, BP, Witherspoon, K, Rosenfeld, JA, van Bon, BWM, Vulto-van Silfhout, AT, Bosco, P, Friend, KL, Baker, C, Buono, S, Vissers, LELM, Schuurs-Hoeijmakers, JH, Hoischen, A, Pfundt, R, Krumm, N, Carvill, GL, Li, D, Amaral, D, Brown, N, Lockhart, PJ, Scheffer, IE, Alberti, A, Shaw, M, Pettinato, R, Tervo, R, de Leeuw, N, Reijnders, MRF, Torchia, BS, Peeters, H, O'Roak, BJ, Fichera, M, Hehir-Kwa, JY, Shendure, J, Mefford, HC, Haan, E, Gecz, J, de Vries, BBA, Romano, C, and Eichler, EE
- Abstract
Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.
- Published
- 2014
5. Nucleotide Excision Repair
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Hoeijmakers, JH, primary
- Published
- 2004
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6. Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis.
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Vorsteveld EE, Van der Made CI, Smeekens SP, Schuurs-Hoeijmakers JH, Astuti G, Diepstra H, Gilissen C, Hoenselaar E, Janssen A, van Roozendaal K, Engelen JS, Steyaert W, Weiss MM, Yntema HG, Mantere T, AlZahrani MS, van Aerde K, Derfalvi B, Faqeih EA, Henriet SSV, van Hoof E, Idressi E, Issekutz TB, Jongmans MCJ, Keski-Filppula R, Krapels I, Te Loo M, Mulders-Manders CM, Ten Oever J, Potjewijd J, Sarhan NT, Slot MC, Terhal PA, Thijs H, Vandersteen A, Vanhoutte EK, van de Veerdonk F, van Well G, Netea MG, Simons A, and Hoischen A
- Subjects
- Humans, High-Throughput Nucleotide Sequencing methods, Cohort Studies, Male, Immune System Diseases genetics, Immune System Diseases diagnosis, Female, Exome Sequencing methods, Exome genetics
- Abstract
While next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use and re-use of exome sequencing is still emerging. We revisited clinical exome data from 1300 IEI patients using an updated in silico IEI gene panel. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8 %. Through systematic reanalysis, we identified variants of interest in 5.2 % of undiagnosed patients, with 76.7 % being (candidate) disease-causing, providing a (candidate) diagnosis in 15.2 % of our cohort. We find a 1.7 percentage point increase in conclusive molecular diagnoses. We find a high degree of actionability in patients with a genetic diagnosis (76.4 %). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in IEI patients, conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation.
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Theil AF, Pines A, Kalayci T, Heredia-Genestar JM, Raams A, Rietveld MH, Sridharan S, Tanis SE, Mulder KW, Büyükbabani N, Karaman B, Uyguner ZO, Kayserili H, Hoeijmakers JH, Lans H, Demmers JA, Pothof J, Altunoglu U, El Ghalbzouri A, and Vermeulen W
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- Humans, Adaptor Proteins, Signal Transducing metabolism, Consanguinity, Mutation, Phenotype, RNA Splicing, Trichothiodystrophy Syndromes genetics, Trichothiodystrophy Syndromes metabolism
- Abstract
The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene-expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2023
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8. Molecular mechanism of extracutaneous tumours in patients with basal cell nevus syndrome.
- Author
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Verkouteren BJ, Roemen GM, Schuurs-Hoeijmakers JH, Abdul Hamid M, van Geel M, Speel EM, and Mosterd K
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- Male, Humans, Basal Cell Nevus Syndrome genetics, Basal Cell Nevus Syndrome pathology, Meningioma, Carcinoma, Basal Cell, Skin Neoplasms genetics, Skin Neoplasms pathology, Meningeal Neoplasms, Leiomyoma
- Abstract
Basal cell nevus syndrome (BCNS) is a rare genetic disorder accompanied by a broad variety of tumours, of which basal cell carcinomas and odontogenic keratocysts are the most common. BCNS is caused by a germline or postzygotic mutation in either PTCH1 or SUFU As BCNS is a rare disease, it is difficult to establish whether less frequently occurring tumours are actually part of the syndrome. In this study, the molecular mechanism behind four extracutaneous tumours in patients with BCNS was elucidated. A leiomyoma of the testis and meningioma were confirmed to be associated with BCNS in two patients by presence of a second mutation or loss of heterozygosity in PTCH1 In a meningioma of a patient with a mosaic postzygotic PTCH1 mutation an association could not be conclusively confirmed. SUFU was probably not involved in the development of a thyroid carcinoma in a patient with a germline SUFU mutation. Hence, we have proven that meningioma and leiomyoma of the testis are rare extracutaneous tumours that are part of BCNS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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9. Complement factor D haplodeficiency is associated with a reduced complement activation speed and diminished bacterial killing.
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Langereis JD, van der Molen RG, de Kat Angelino C, Henriet SS, de Jonge MI, Joosten I, Simons A, Schuurs-Hoeijmakers JH, van Deuren M, van Aerde K, and van der Flier M
- Abstract
Objectives: Complete deficiency of alternative pathway (AP) complement factors, explained by homozygous mutations, is a well-known risk factor for invasive bacterial infections; however, this is less obvious for heterozygous mutations. We describe two siblings with a heterozygous NM_001928.3(CFD):c.125C>A p.(Ser42*) mutation in the complement factor D (fD) gene having a history of recurrent bacterial infections. We determined the effect of heterozygous fD deficiency on AP complement activity., Methods: We determined the effect of fD levels on complement activation as measured by AP activity, complement C3 binding to the bacterial surface of Neisseria meningitidis (Nm), Streptococcus pneumoniae (Sp) and non-typeable Haemophilus influenzae (NTHi), and complement-mediated killing of Nm and NTHi. In addition, we measured the effect of vaccination of complement C3 binding to the bacterial surface and killing of Nm., Results: Reconstitution of fD-deficient serum with fD increased AP activity in a dose- and time-dependent way. Reconstitution of patient serum with fD to normal levels increased complement C3 binding to Sp, Nm and NTHi, as well as complement-mediated killing of Nm and NTHi. Vaccination increased complement C3 binding and resulted in complete killing of Nm without fD reconstitution., Conclusion: We conclude that low fD serum levels (< 0.5 μg mL
-1 ) lead to a reduced speed of complement activation, which results in diminished bacterial killing, consistent with recurrent bacterial infections observed in our index patients. Specific antibodies induced by vaccination are able to overcome the diminished bacterial killing capacity in patients with low fD levels., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2021
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10. DNA damage-induced replication stress results in PA200-proteasome-mediated degradation of acetylated histones.
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Mandemaker IK, Geijer ME, Kik I, Bezstarosti K, Rijkers E, Raams A, Janssens RC, Lans H, Hoeijmakers JH, Demmers JA, Vermeulen W, and Marteijn JA
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- Acetylation, Amino Acid Sequence genetics, DNA Repair genetics, DNA Replication genetics, Histones genetics, Humans, Proteolysis, Ubiquitination genetics, Chromatin genetics, DNA Damage genetics, Nuclear Proteins genetics, Proteasome Endopeptidase Complex genetics
- Abstract
Histone acetylation influences protein interactions and chromatin accessibility and plays an important role in the regulation of transcription, replication, and DNA repair. Conversely, DNA damage affects these crucial cellular processes and induces changes in histone acetylation. However, a comprehensive overview of the effects of DNA damage on the histone acetylation landscape is currently lacking. To quantify changes in histone acetylation, we developed an unbiased quantitative mass spectrometry analysis on affinity-purified acetylated histone peptides, generated by differential parallel proteolysis. We identify a large number of histone acetylation sites and observe an overall reduction of acetylated histone residues in response to DNA damage, indicative of a histone-wide loss of acetyl modifications. This decrease is mainly caused by DNA damage-induced replication stress coupled to specific proteasome-dependent loss of acetylated histones. Strikingly, this degradation of acetylated histones is independent of ubiquitylation but requires the PA200-proteasome activator, a complex that specifically targets acetylated histones for degradation. The uncovered replication stress-induced degradation of acetylated histones represents an important chromatin-modifying response to cope with replication stress., (© 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2018
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11. Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson's disease.
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Milanese C, Cerri S, Ulusoy A, Gornati SV, Plat A, Gabriels S, Blandini F, Di Monte DA, Hoeijmakers JH, and Mastroberardino PG
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- Animals, Ataxia Telangiectasia Mutated Proteins metabolism, Cell Line, Tumor, DNA Damage, Disease Models, Animal, Dopaminergic Neurons metabolism, Histones genetics, Histones metabolism, Humans, Mice, Mice, Inbred C57BL, Mitochondria metabolism, Parkinson Disease metabolism, Reactive Oxygen Species metabolism, Substantia Nigra metabolism, Tumor Suppressor p53-Binding Protein 1 genetics, Tumor Suppressor p53-Binding Protein 1 metabolism, alpha-Synuclein genetics, DNA Repair, Parkinson Disease pathology, Substantia Nigra pathology, alpha-Synuclein metabolism
- Abstract
The involvement of DNA damage and repair in aging processes is well established. Aging is an unequivocal risk factor for chronic neurodegenerative diseases, underscoring the relevance of investigations into the role that DNA alterations may have in the pathogenesis of these diseases. Consistently, even moderate impairment of DNA repair systems facilitates the onset of pathological features typical of PD that include derangement of the dopaminergic system, mitochondrial dysfunction, and alpha-synuclein stress. The latter establishes a connection between reduced DNA repair capacity and a cardinal feature of PD, alpha-synuclein pathology. It remains to be determined, however, whether alpha-synuclein stress activates in vivo the canonical signaling cascade associated with DNA damage, which is centered on the kinase ATM and substrates such as γH2Ax and 53BP1. Addressing these issues would shed light on age-related mechanisms impinging upon PD pathogenesis and neurodegeneration in particular. We analyzed two different synucleinopathy PD mouse models based either on intranigral delivery of AAV-expressing human alpha-synuclein, or intrastriatal injection of human alpha-synuclein pre-formed fibrils. In both cases, we detected a significant increase in γH2AX and 53BP1 foci, and in phospho-ATM immunoreactivity in dopaminergic neurons, which collectively indicate DNA damage and activation of the DNA damage response. Mechanistic experiments in cell cultures indicate that activation of the DNA damage response is caused, at least in part, by pro-oxidant species because it is prevented by exogenous or endogenous antioxidants, which also rescue mitochondrial anomalies caused by proteotoxic alpha-synuclein. These in vivo and in vitro findings reveal that the cellular stress mediated by alpha-synuclein-a pathological hallmark in PD-elicits DNA damage and activates the DNA damage response. The toxic cascade leading to DNA damage involves oxidant stress and mitochondrial dysfunction The data underscore the importance of DNA quality control for preservation of neuronal integrity and protection against neurodegenerative processes.
- Published
- 2018
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12. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.
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Jansen S, Hoischen A, Coe BP, Carvill GL, Van Esch H, Bosch DGM, Andersen UA, Baker C, Bauters M, Bernier RA, van Bon BW, Claahsen-van der Grinten HL, Gecz J, Gilissen C, Grillo L, Hackett A, Kleefstra T, Koolen D, Kvarnung M, Larsen MJ, Marcelis C, McKenzie F, Monin ML, Nava C, Schuurs-Hoeijmakers JH, Pfundt R, Steehouwer M, Stevens SJC, Stumpel CT, Vansenne F, Vinci M, van de Vorst M, Vries P, Witherspoon K, Veltman JA, Brunner HG, Mefford HC, Romano C, Vissers LELM, Eichler EE, and de Vries BBA
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- Adolescent, Adult, Child, Female, Genetic Testing standards, Haploinsufficiency, Humans, Male, Reproducibility of Results, Sequence Analysis, DNA methods, Sequence Analysis, DNA standards, Syndrome, Genetic Testing methods, Genotype, Intellectual Disability genetics, Intracellular Signaling Peptides and Proteins genetics, Overweight genetics
- Abstract
Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.
- Published
- 2018
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13. DNA damage-induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8-RNF168 pathway.
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Mandemaker IK, van Cuijk L, Janssens RC, Lans H, Bezstarosti K, Hoeijmakers JH, Demmers JA, Vermeulen W, and Marteijn JA
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- DNA-Binding Proteins genetics, HeLa Cells, Histones genetics, Humans, Tumor Suppressor Proteins genetics, Ubiquitin-Protein Ligases genetics, DNA Damage, DNA-Binding Proteins metabolism, Histones metabolism, Signal Transduction radiation effects, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitination, Ultraviolet Rays
- Abstract
The DNA damage response (DDR), comprising distinct repair and signalling pathways, safeguards genomic integrity. Protein ubiquitylation is an important regulatory mechanism of the DDR. To study its role in the UV-induced DDR, we characterized changes in protein ubiquitylation following DNA damage using quantitative di-Gly proteomics. Interestingly, we identified multiple sites of histone H1 that are ubiquitylated upon UV-damage. We show that UV-dependent histone H1 ubiquitylation at multiple lysines is mediated by the E3-ligase HUWE1. Recently, it was shown that poly-ubiquitylated histone H1 is an important signalling intermediate in the double strand break response. This poly-ubiquitylation is dependent on RNF8 and Ubc13 which extend pre-existing ubiquitin modifications to K63-linked chains. Here we demonstrate that HUWE1 depleted cells showed reduced recruitment of RNF168 and 53BP1 to sites of DNA damage, two factors downstream of RNF8 mediated histone H1 poly-ubiquitylation, while recruitment of MDC1, which act upstream of histone H1 ubiquitylation, was not affected. Our data show that histone H1 is a prominent target for ubiquitylation after UV-induced DNA damage. Our data are in line with a model in which HUWE1 primes histone H1 with ubiquitin to allow ubiquitin chain elongation by RNF8, thereby stimulating the RNF8-RNF168 mediated DDR.
- Published
- 2017
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14. Frontline Science: Tryptophan restriction arrests B cell development and enhances microbial diversity in WT and prematurely aging Ercc1 -/Δ7 mice.
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van Beek AA, Hugenholtz F, Meijer B, Sovran B, Perdijk O, Vermeij WP, Brandt RM, Barnhoorn S, Hoeijmakers JH, de Vos P, Leenen PJ, Hendriks RW, and Savelkoul HF
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- Animals, Bacteria metabolism, Bone Marrow metabolism, Diet, Female, Gastrointestinal Tract microbiology, Immunologic Memory, Lymph Nodes cytology, Lymphocyte Count, Mice, Inbred C57BL, Spleen cytology, T-Lymphocytes, Regulatory metabolism, Aging, Premature immunology, Aging, Premature microbiology, B-Lymphocytes cytology, DNA-Binding Proteins metabolism, Endonucleases metabolism, Microbiota, Tryptophan metabolism
- Abstract
With aging, tryptophan metabolism is affected. Tryptophan has a crucial role in the induction of immune tolerance and the maintenance of gut microbiota. We, therefore, studied the effect of dietary tryptophan restriction in young wild-type (WT) mice (118-wk life span) and in DNA-repair deficient, premature-aged ( Ercc1
-/Δ7 ) mice (20-wk life span). First, we found that the effect of aging on the distribution of B and T cells in bone marrow (BM) and in the periphery of 16-wk-old Ercc1-/Δ7 mice was comparable to that in 18-mo-old WT mice. Dietary tryptophan restriction caused an arrest of B cell development in the BM, accompanied by diminished B cell frequencies in the periphery. In general, old Ercc1-/Δ7 mice showed similar responses to tryptophan restriction compared with young WT mice, indicative of age-independent effects. Dietary tryptophan restriction increased microbial diversity and made the gut microbiota composition of old Ercc1-/Δ7 mice more similar to that of young WT mice. The decreased abundances of Alistipes and Akkermansia spp. after dietary tryptophan restriction correlated significantly with decreased B cell precursor numbers. In conclusion, we report that dietary tryptophan restriction arrests B cell development and concomitantly changes gut microbiota composition. Our study suggests a beneficial interplay between dietary tryptophan, B cell development, and gut microbial composition on several aspects of age-induced changes., (© Society for Leukocyte Biology.)- Published
- 2017
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15. A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction.
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Jongbloed F, Saat TC, Verweij M, Payan-Gomez C, Hoeijmakers JH, van den Engel S, van Oostrom CT, Ambagtsheer G, Imholz S, Pennings JL, van Steeg H, IJzermans JN, Dollé ME, and de Bruin RW
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- Animals, Forkhead Box Protein O3 genetics, Forkhead Box Protein O3 metabolism, HMGA1a Protein genetics, HMGA1a Protein metabolism, Hepatocyte Nuclear Factor 4 genetics, Hepatocyte Nuclear Factor 4 metabolism, Kidney pathology, Male, Mice, Mice, Inbred C57BL, Principal Component Analysis, Reperfusion Injury metabolism, Reperfusion Injury pathology, Transcriptome, Caloric Restriction, Diet, Protein-Restricted, Kidney metabolism
- Abstract
During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.
- Published
- 2017
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16. After surviving cancer, what about late life effects of the cure?
- Author
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Nonnekens J and Hoeijmakers JH
- Subjects
- Humans, Disease Progression, Neoplasms
- Published
- 2017
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17. Supplementation with Lactobacillus plantarum WCFS1 Prevents Decline of Mucus Barrier in Colon of Accelerated Aging Ercc1 -/Δ7 Mice.
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van Beek AA, Sovran B, Hugenholtz F, Meijer B, Hoogerland JA, Mihailova V, van der Ploeg C, Belzer C, Boekschoten MV, Hoeijmakers JH, Vermeij WP, de Vos P, Wells JM, Leenen PJ, Nicoletti C, Hendriks RW, and Savelkoul HF
- Abstract
Although it is clear that probiotics improve intestinal barrier function, little is known about the effects of probiotics on the aging intestine. We investigated effects of 10-week bacterial supplementation of Lactobacillus plantarum WCFS1, Lactobacillus casei BL23, or Bifidobacterium breve DSM20213 on gut barrier and immunity in 16-week-old accelerated aging Ercc1
-/Δ7 mice, which have a median lifespan of ~20 weeks, and their wild-type littermates. The colonic barrier in Ercc1-/Δ7 mice was characterized by a thin (< 10 μm) mucus layer. L. plantarum prevented this decline in mucus integrity in Ercc1-/Δ7 mice, whereas B. breve exacerbated it. Bacterial supplementations affected the expression of immune-related genes, including Toll-like receptor 4. Regulatory T cell frequencies were increased in the mesenteric lymph nodes of L. plantarum - and L. casei -treated Ercc1-/Δ7 mice. L. plantarum - and L. casei -treated Ercc1-/Δ7 mice showed increased specific antibody production in a T cell-dependent immune response in vivo . By contrast, the effects of bacterial supplementation on wild-type control mice were negligible. Thus, supplementation with L. plantarum - but not with L. casei and B. breve - prevented the decline in the mucus barrier in Ercc1-/Δ7 mice. Our data indicate that age is an important factor influencing beneficial or detrimental effects of candidate probiotics. These findings also highlight the need for caution in translating beneficial effects of probiotics observed in young animals or humans to the elderly.- Published
- 2016
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18. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.
- Author
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Vermeij WP, Dollé ME, Reiling E, Jaarsma D, Payan-Gomez C, Bombardieri CR, Wu H, Roks AJ, Botter SM, van der Eerden BC, Youssef SA, Kuiper RV, Nagarajah B, van Oostrom CT, Brandt RM, Barnhoorn S, Imholz S, Pennings JL, de Bruin A, Gyenis Á, Pothof J, Vijg J, van Steeg H, and Hoeijmakers JH
- Subjects
- Animals, Brain physiology, DNA Damage, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Endonucleases deficiency, Endonucleases genetics, Female, Male, Mice, Neurodegenerative Diseases genetics, Neurodegenerative Diseases prevention & control, Nuclear Proteins deficiency, Nuclear Proteins genetics, Transcription Factors deficiency, Transcription Factors genetics, Transcriptome, Aging genetics, Caloric Restriction, DNA Repair genetics, Diet, Reducing, Genomic Instability
- Abstract
Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1
∆/- ) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg-/- (also known as Ercc5-/- ) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1∆/- mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/- mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general., Competing Interests: The authors declare no competing financial interests.- Published
- 2016
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19. Duplications of SLC1A3: Associated with ADHD and autism.
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van Amen-Hellebrekers CJ, Jansen S, Pfundt R, Schuurs-Hoeijmakers JH, Koolen DA, Marcelis CL, de Leeuw N, and de Vries BB
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- Child, Child, Preschool, Chromosomes, Human, Pair 5, Female, Genetic Association Studies, Genome-Wide Association Study, Humans, Infant, Male, Oligonucleotide Array Sequence Analysis, Pedigree, Phenotype, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity genetics, Autistic Disorder genetics, Excitatory Amino Acid Transporter 1 genetics, Gene Duplication
- Abstract
We report four patients with a similar gain in 5p13.2 encompassing a single gene: SLC1A3. Behavioural problems resembling ADHD and/or autism-like features are observed which is in line with the glial glutamate transporter role of SLC1A3. We consider an association between SLC1A3 and the behavioural problems which can also be considered a contributing factor to behavioural problems in larger duplications overlapping the 5p13 microduplication syndrome region., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
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20. De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.
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Lugtenberg D, Reijnders MR, Fenckova M, Bijlsma EK, Bernier R, van Bon BW, Smeets E, Vulto-van Silfhout AT, Bosch D, Eichler EE, Mefford HC, Carvill GL, Bongers EM, Schuurs-Hoeijmakers JH, Ruivenkamp CA, Santen GW, van den Maagdenberg AM, Peeters-Scholte CM, Kuenen S, Verstreken P, Pfundt R, Yntema HG, de Vries PF, Veltman JA, Hoischen A, Gilissen C, de Vries BB, Schenck A, Kleefstra T, and Vissers LE
- Subjects
- Adolescent, Animals, Carrier Proteins metabolism, Child, Child, Preschool, Craniofacial Abnormalities diagnosis, Drosophila genetics, Drosophila physiology, Drosophila Proteins metabolism, Female, Habituation, Psychophysiologic, Humans, Intellectual Disability diagnosis, Learning, Learning Disabilities diagnosis, Male, Phenotype, Syndrome, Young Adult, Adaptor Proteins, Signal Transducing genetics, Carrier Proteins genetics, Craniofacial Abnormalities genetics, Drosophila Proteins genetics, Intellectual Disability genetics, Learning Disabilities genetics, Mutation
- Abstract
Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.
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- 2016
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21. Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease.
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Sepe S, Milanese C, Gabriels S, Derks KW, Payan-Gomez C, van IJcken WF, Rijksen YM, Nigg AL, Moreno S, Cerri S, Blandini F, Hoeijmakers JH, and Mastroberardino PG
- Subjects
- Animals, Corpus Striatum pathology, Corpus Striatum ultrastructure, DNA-Binding Proteins metabolism, Dopaminergic Neurons pathology, Dopaminergic Neurons ultrastructure, Endonucleases metabolism, Fibroblasts metabolism, Fibroblasts pathology, Humans, Mice, Aging pathology, DNA Repair, Parkinson Disease pathology
- Abstract
The underlying relation between Parkinson's disease (PD) etiopathology and its major risk factor, aging, is largely unknown. In light of the causative link between genome stability and aging, we investigate a possible nexus between DNA damage accumulation, aging, and PD by assessing aging-related DNA repair pathways in laboratory animal models and humans. We demonstrate that dermal fibroblasts from PD patients display flawed nucleotide excision repair (NER) capacity and that Ercc1 mutant mice with mildly compromised NER exhibit typical PD-like pathological alterations, including decreased striatal dopaminergic innervation, increased phospho-synuclein levels, and defects in mitochondrial respiration. Ercc1 mouse mutants are also more sensitive to the prototypical PD toxin MPTP, and their transcriptomic landscape shares important similarities with that of PD patients. Our results demonstrate that specific defects in DNA repair impact the dopaminergic system and are associated with human PD pathology and might therefore constitute an age-related risk factor for PD., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2016
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22. Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.
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Peters B, Schuurs-Hoeijmakers JH, Fuijkschot J, Reimer A, van der Flier M, Lugtenberg D, and Hoppenreijs EP
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- Arthropathy, Neurogenic genetics, Child, Consanguinity, Coxa Vara genetics, Female, Hand Deformities, Congenital genetics, Homozygote, Humans, Protein-Losing Enteropathies genetics, Synovitis genetics, Arthropathy, Neurogenic complications, Coxa Vara complications, Hand Deformities, Congenital complications, Protein-Losing Enteropathies complications, Synovitis complications
- Abstract
Background: Camptodactyly-arthropathy-coxa vara-pericarditis (CACP, OMIM: #208250) syndrome is a rare autosomal recessive disease that can be difficult to recognise not only because of its wide clinical variability but also because of its clinical resemblance to juvenile idiopathic arthritis (JIA). PRG4 is the only gene so far known to be associated with CACP syndrome. Children with CACP syndrome lack the glycoprotein lubricin due to recessive mutations in PRG4. Lubricin serves as a lubricant in joints, tendons and visceral cavities (pleural cavity, pericardium) and inhibits synovial proliferation. Children with CACP syndrome suffer from congenital camptodactyly, arthropathy, coxa vara and sometimes pericarditis. This report concerns a child with CACP syndrome complicated by protein-losing enteropathy (PLE), caused by constrictive pericarditis and so contributes to knowledge of the presentation of CACP syndrome., Case Presentation: A 10- year-old girl with consanguineous parents suffered from congenital camptodactyly and progressive swollen and painful joints. Her father and his sister had similar childhood-onset joint complaints. Laboratory tests showed no signs of inflammation but showed persistent low protein- and IgG- levels, indicating a secondary immunodeficiency. Increased alpha antitrypsin clearance confirmed PLE. Abdominal ultrasound with Doppler showed hepatomegaly and portal hypertension. Echocardiography suggested constrictive pericarditis. However, heart catheterization could not confirm this. Ultrasound and X-ray examination of the joints combined with a puncture of the synovial fluid were performed. These results, combined with the clinical presentation and the consanguinity, suggested CACP syndrome. Due to excessive enteral protein losses, the patient was treated with Cotrimoxazol prophylaxis and immunoglobulin supplements. These supplements were inadequate to achieve normal IgG values. As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results. Genetic testing in our patient was complicated but revealed a pathogenic mutation within the repeat sequence in exon 7 of the PRG4 gene., Conclusion: PLE resulting from constrictive pericarditis can be a complication of CACP syndrome. As serious complications can arise from the resulting secondary immunodeficiency, we recommend regular evaluation of clinical symptoms of constrictive pericarditis and PLE in children with CACP syndrome.
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- 2016
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23. Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.
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Kruiswijk F, Hasenfuss SC, Sivapatham R, Baar MP, Putavet D, Naipal KA, van den Broek NJ, Kruit W, van der Spek PJ, van Gent DC, Brenkman AB, Campisi J, Burgering BM, Hoeijmakers JH, and de Keizer PL
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- Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Indoles administration & dosage, Melanoma genetics, Melanoma pathology, Molecular Targeted Therapy, Mutation, Neoplasm Metastasis, Protein Kinase Inhibitors administration & dosage, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Signal Transduction, Sulfonamides administration & dosage, Vemurafenib, Forkhead Box Protein M1 genetics, Melanoma drug therapy, NIMA-Interacting Peptidylprolyl Isomerase genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAF(V600E), the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAF(V600E)-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAF(V600E)-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.
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- 2016
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24. Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging.
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Visser WE, Bombardieri CR, Zevenbergen C, Barnhoorn S, Ottaviani A, van der Pluijm I, Brandt R, Kaptein E, van Heerebeek R, van Toor H, Garinis GA, Peeters RP, Medici M, van Ham W, Vermeij WP, de Waard MC, de Krijger RR, Boelen A, Kwakkel J, Kopchick JJ, List EO, Melis JP, Darras VM, Dollé ME, van der Horst GT, Hoeijmakers JH, and Visser TJ
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- Aging genetics, Animals, Hypothyroidism genetics, Hypothyroidism metabolism, Iodide Peroxidase genetics, Liver metabolism, Mice, Mice, Knockout, Organ Specificity, Thyroid Hormones genetics, Aging metabolism, DNA Damage, Iodide Peroxidase metabolism, Thyroid Hormones metabolism
- Abstract
DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.
- Published
- 2016
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25. Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.
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Stessman HAF, Willemsen MH, Fenckova M, Penn O, Hoischen A, Xiong B, Wang T, Hoekzema K, Vives L, Vogel I, Brunner HG, van der Burgt I, Ockeloen CW, Schuurs-Hoeijmakers JH, Klein Wassink-Ruiter JS, Stumpel C, Stevens SJC, Vles HS, Marcelis CM, van Bokhoven H, Cantagrel V, Colleaux L, Nicouleau M, Lyonnet S, Bernier RA, Gerdts J, Coe BP, Romano C, Alberti A, Grillo L, Scuderi C, Nordenskjöld M, Kvarnung M, Guo H, Xia K, Piton A, Gerard B, Genevieve D, Delobel B, Lehalle D, Perrin L, Prieur F, Thevenon J, Gecz J, Shaw M, Pfundt R, Keren B, Jacquette A, Schenck A, Eichler EE, and Kleefstra T
- Subjects
- Adolescent, Adult, Animals, Autism Spectrum Disorder diagnosis, Child, Child, Preschool, Cohort Studies, Down-Regulation, Drosophila genetics, Drosophila Proteins genetics, Drosophila Proteins metabolism, Exome, Female, Gene Knockdown Techniques, Genome-Wide Association Study, Humans, Infant, Intellectual Disability diagnosis, Language Development Disorders diagnosis, Language Development Disorders genetics, Linear Models, Male, Microcephaly diagnosis, Microcephaly genetics, Mutation, Phenotype, Transcription Factors genetics, Transcription Factors metabolism, Autism Spectrum Disorder genetics, Intellectual Disability genetics, Transposases genetics
- Abstract
Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2016
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26. TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.
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Ba W, Yan Y, Reijnders MR, Schuurs-Hoeijmakers JH, Feenstra I, Bongers EM, Bosch DG, De Leeuw N, Pfundt R, Gilissen C, De Vries PF, Veltman JA, Hoischen A, Mefford HC, Eichler EE, Vissers LE, Nadif Kasri N, and De Vries BB
- Subjects
- Adult, Animals, Autistic Disorder metabolism, Autistic Disorder pathology, Child, Female, Gene Expression, Guanine Nucleotide Exchange Factors deficiency, Hippocampus metabolism, Hippocampus pathology, Humans, Intellectual Disability metabolism, Intellectual Disability pathology, Male, Neurogenesis, Neurons pathology, Primary Cell Culture, Protein Serine-Threonine Kinases deficiency, Psychomotor Agitation metabolism, Psychomotor Agitation pathology, Rats, Sequence Analysis, DNA, Severity of Illness Index, Synapses pathology, Autistic Disorder genetics, Guanine Nucleotide Exchange Factors genetics, Intellectual Disability genetics, Mutation, Neurons metabolism, Protein Serine-Threonine Kinases genetics, Psychomotor Agitation genetics, Synapses metabolism
- Abstract
Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2016
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27. Altered lipid metabolism in the aging kidney identified by three layered omic analysis.
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Braun F, Rinschen MM, Bartels V, Frommolt P, Habermann B, Hoeijmakers JH, Schumacher B, Dollé ME, Müller RU, Benzing T, Schermer B, and Kurschat CE
- Subjects
- Acid Ceramidase metabolism, Animals, Ceramides metabolism, Mass Spectrometry, Mice, Inbred C57BL, Phenotype, Phospholipids metabolism, Proteomics, Aging metabolism, Kidney metabolism, Lipid Metabolism
- Abstract
Aging-associated diseases and their comorbidities affect the life of a constantly growing proportion of the population in developed countries. At the center of these comorbidities are changes of kidney structure and function as age-related chronic kidney disease predisposes to the development of cardiovascular diseases such as stroke, myocardial infarction or heart failure. To detect molecular mechanisms involved in kidney aging, we analyzed gene expression profiles of kidneys from adult and aged wild-type mice by transcriptomic, proteomic and targeted lipidomic methodologies. Interestingly, transcriptome and proteome analyses revealed differential expression of genes primarily involved in lipid metabolism and immune response. Additional lipidomic analyses uncovered significant age-related differences in the total amount of phosphatidylethanolamines, phosphatidylcholines and sphingomyelins as well as in subspecies of phosphatidylserines and ceramides with age. By integration of these datasets we identified Aldh1a1, a key enzyme in vitamin A metabolism specifically expressed in the medullary ascending limb, as one of the most prominent upregulated proteins in old kidneys. Moreover, ceramidase Asah1 was highly expressed in aged kidneys, consistent with a decrease in ceramide C16. In summary, our data suggest that changes in lipid metabolism are involved in the process of kidney aging and in the development of chronic kidney disease.
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- 2016
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28. Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
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Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH, Greville-Heygate S, Hanson-Kahn A, Bernstein JA, Glass J, Chitayat D, Burrow TA, Husami A, Collins K, Wusik K, van der Aa N, Kooy F, Brown KT, Gadzicki D, Kini U, Alvarez S, Fernández-Jaén A, McGehee F, Selby K, Tarailo-Graovac M, Van Allen M, van Karnebeek CD, Stavropoulos DJ, Marshall CR, Merico D, Gregor A, Zweier C, Hopkin RJ, Chu YW, Chung BH, de Vries BB, Devriendt K, Hurles ME, and Brunner HG
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple drug therapy, Abnormalities, Multiple pathology, Adolescent, Anticonvulsants therapeutic use, Child, Child, Preschool, Facies, Failure to Thrive diagnosis, Failure to Thrive drug therapy, Failure to Thrive genetics, Failure to Thrive pathology, Female, Gene Expression, Humans, Intellectual Disability diagnosis, Intellectual Disability drug therapy, Intellectual Disability pathology, Male, Muscle Hypotonia diagnosis, Muscle Hypotonia drug therapy, Muscle Hypotonia genetics, Muscle Hypotonia pathology, Seizures diagnosis, Seizures drug therapy, Seizures pathology, Severity of Illness Index, Syndrome, Young Adult, Abnormalities, Multiple genetics, Intellectual Disability genetics, Point Mutation, Seizures genetics, Vesicular Transport Proteins genetics
- Abstract
We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases., (© 2016 Wiley Periodicals, Inc.)
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- 2016
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29. Tumor slice culture system to assess drug response of primary breast cancer.
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Naipal KA, Verkaik NS, Sánchez H, van Deurzen CH, den Bakker MA, Hoeijmakers JH, Kanaar R, Vreeswijk MP, Jager A, and van Gent DC
- Subjects
- Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms pathology, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Drug Resistance, Neoplasm genetics, Female, Fluorouracil administration & dosage, Humans, Precision Medicine, Tumor Cells, Cultured drug effects, Antineoplastic Agents administration & dosage, Breast Neoplasms drug therapy, Drug Screening Assays, Antitumor, Tissue Culture Techniques methods
- Abstract
Background: The high incidence of breast cancer has sparked the development of novel targeted and personalized therapies. Personalization of cancer treatment requires reliable prediction of chemotherapy responses in individual patients. Effective selection can prevent unnecessary treatment that would mainly result in the unwanted side effects of the therapy. This selection can be facilitated by characterization of individual tumors using robust and specific functional assays, which requires development of powerful ex vivo culture systems and procedures to analyze the response to treatment., Methods: We optimized culture methods for primary breast tumor samples that allowed propagation of tissue ex vivo. We combined several tissue culture strategies, including defined tissue slicing technology, growth medium optimization and use of a rotating platform to increase nutrient exchange., Results: We could maintain tissue cultures for at least 7 days without losing tissue morphology, viability or cell proliferation. We also developed methods to determine the cytotoxic response of individual tumors to the chemotherapeutic treatment FAC (5-FU, Adriamycin [Doxorubicin] and Cyclophosphamide). Using this tool we designated tumors as sensitive or resistant and distinguished a clinically proven resistant tumor from other tumors., Conclusion: This method defines conditions that allow ex vivo testing of individual tumor responses to anti-cancer drugs and therefore might improve personalization of breast cancer treatment.
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- 2016
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30. Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options.
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Vermeij WP, Hoeijmakers JH, and Pothof J
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- Animals, Disease Models, Animal, Humans, Mice, Syndrome, Aging genetics, Genomic Instability genetics
- Abstract
Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology.
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- 2016
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31. Phosphodiesterase 1 regulation is a key mechanism in vascular aging.
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Bautista Niño PK, Durik M, Danser AH, de Vries R, Musterd-Bhaggoe UM, Meima ME, Kavousi M, Ghanbari M, Hoeijmakers JH, O'Donnell CJ, Franceschini N, Janssen GM, De Mey JG, Liu Y, Shanahan CM, Franco OH, Dehghan A, and Roks AJ
- Subjects
- Aging genetics, Animals, Blood Pressure, Carotid Arteries enzymology, Carotid Arteries pathology, Carotid Artery Diseases enzymology, Carotid Artery Diseases genetics, Carotid Artery Diseases pathology, Carotid Intima-Media Thickness, Cells, Cultured, Cellular Senescence, Cyclic GMP metabolism, Cyclic Nucleotide Phosphodiesterases, Type 1 antagonists & inhibitors, Cyclic Nucleotide Phosphodiesterases, Type 1 genetics, Cyclic Nucleotide Phosphodiesterases, Type 5 genetics, Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Dose-Response Relationship, Drug, Endonucleases deficiency, Endonucleases genetics, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hydrolysis, Hyperplasia, Hypertension enzymology, Hypertension genetics, Hypertension physiopathology, In Vitro Techniques, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular drug effects, Myocytes, Smooth Muscle drug effects, Phenotype, Phosphodiesterase 5 Inhibitors pharmacology, Polymorphism, Single Nucleotide, Second Messenger Systems, Vasodilator Agents pharmacology, Aging metabolism, Cyclic Nucleotide Phosphodiesterases, Type 1 metabolism, Muscle, Smooth, Vascular enzymology, Myocytes, Smooth Muscle enzymology, Vasodilation drug effects
- Abstract
Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; β=0.28, P=2.47×10(-5)) and carotid intima-media thickness (cIMT; β=-0.0061, P=2.89×10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy., (© 2015 Authors; published by Portland Press Limited.)
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- 2015
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32. MARK-AGE biomarkers of ageing.
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Bürkle A, Moreno-Villanueva M, Bernhard J, Blasco M, Zondag G, Hoeijmakers JH, Toussaint O, Grubeck-Loebenstein B, Mocchegiani E, Collino S, Gonos ES, Sikora E, Gradinaru D, Dollé M, Salmon M, Kristensen P, Griffiths HR, Libert C, Grune T, Breusing N, Simm A, Franceschi C, Capri M, Talbot D, Caiafa P, Friguet B, Slagboom PE, Hervonen A, Hurme M, and Aspinall R
- Subjects
- European Union, Female, Humans, Male, Aging metabolism, Biomarkers metabolism
- Abstract
Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)
- Published
- 2015
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33. Check, Check …Triple Check: Multi-Step DNA Lesion Identification by Nucleotide Excision Repair.
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Marteijn JA, Hoeijmakers JH, and Vermeulen W
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- Animals, Humans, DNA Adducts genetics, DNA-Binding Proteins physiology, Transcription Factor TFIIH physiology, Xeroderma Pigmentosum Group A Protein physiology
- Abstract
In this issue, Li et al. (2015) uncover roles for the XPB and XPD helicases and for XPA during damage verification in nucleotide excision repair, supporting a novel tripartite damage checking mechanism that combines extreme versatility with narrow specificity., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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34. The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex.
- Author
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Faridounnia M, Wienk H, Kovačič L, Folkers GE, Jaspers NG, Kaptein R, Hoeijmakers JH, and Boelens R
- Subjects
- Amino Acid Sequence, DNA-Binding Proteins chemistry, Dimerization, Endonucleases chemistry, Humans, Models, Chemical, Molecular Sequence Data, Sequence Homology, Amino Acid, Cockayne Syndrome genetics, DNA Repair genetics, DNA-Binding Proteins genetics, Endonucleases genetics, Point Mutation
- Abstract
The ERCC1-XPF heterodimer, a structure-specific DNA endonuclease, is best known for its function in the nucleotide excision repair (NER) pathway. The ERCC1 point mutation F231L, located at the hydrophobic interaction interface of ERCC1 (excision repair cross-complementation group 1) and XPF (xeroderma pigmentosum complementation group F), leads to severe NER pathway deficiencies. Here, we analyze biophysical properties and report the NMR structure of the complex of the C-terminal tandem helix-hairpin-helix domains of ERCC1-XPF that contains this mutation. The structures of wild type and the F231L mutant are very similar. The F231L mutation results in only a small disturbance of the ERCC1-XPF interface, where, in contrast to Phe(231), Leu(231) lacks interactions stabilizing the ERCC1-XPF complex. One of the two anchor points is severely distorted, and this results in a more dynamic complex, causing reduced stability and an increased dissociation rate of the mutant complex as compared with wild type. These data provide a biophysical explanation for the severe NER deficiencies caused by this mutation., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
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35. The core spliceosome as target and effector of non-canonical ATM signalling.
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Tresini M, Warmerdam DO, Kolovos P, Snijder L, Vrouwe MG, Demmers JA, van IJcken WF, Grosveld FG, Medema RH, Hoeijmakers JH, Mullenders LH, Vermeulen W, and Marteijn JA
- Subjects
- Alternative Splicing physiology, Cell Line, Chromatin metabolism, DNA-Directed RNA Polymerases metabolism, Enzyme Activation, Humans, Ultraviolet Rays, Ataxia Telangiectasia Mutated Proteins metabolism, DNA Damage physiology, Signal Transduction, Spliceosomes metabolism
- Abstract
In response to DNA damage, tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signalling pathways coordinate these processes, partly by propagating gene-expression-modulating signals. DNA damage influences not only the abundance of messenger RNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level. Our findings define R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells, and highlight a key role for spliceosome displacement in this process.
- Published
- 2015
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36. Attenuated XPC expression is not associated with impaired DNA repair in bladder cancer.
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Naipal KA, Raams A, Bruens ST, Brandsma I, Verkaik NS, Jaspers NG, Hoeijmakers JH, van Leenders GJ, Pothof J, Kanaar R, Boormans J, and van Gent DC
- Subjects
- DNA genetics, DNA-Binding Proteins analysis, Humans, Tumor Cells, Cultured, Urinary Bladder metabolism, Urinary Bladder Neoplasms pathology, Xeroderma Pigmentosum pathology, DNA Repair, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, Urinary Bladder pathology, Urinary Bladder Neoplasms genetics, Xeroderma Pigmentosum genetics
- Abstract
Bladder cancer has a high incidence with significant morbidity and mortality. Attenuated expression of the DNA damage response protein Xeroderma Pigmentosum complementation group C (XPC) has been described in bladder cancer. XPC plays an essential role as the main initiator and damage-detector in global genome nucleotide excision repair (NER) of UV-induced lesions, bulky DNA adducts and intrastrand crosslinks, such as those made by the chemotherapeutic agent Cisplatin. Hence, XPC protein might be an informative biomarker to guide personalized therapy strategies in a subset of bladder cancer cases. Therefore, we measured the XPC protein expression level and functional NER activity of 36 bladder tumors in a standardized manner. We optimized conditions for dissociation and in vitro culture of primary bladder cancer cells and confirmed attenuated XPC expression in approximately 40% of the tumors. However, NER activity was similar to co-cultured wild type cells in all but one of 36 bladder tumors. We conclude, that (i) functional NER deficiency is a relatively rare phenomenon in bladder cancer and (ii) XPC protein levels are not useful as biomarker for NER activity in these tumors.
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- 2015
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37. Deciphering the RNA landscape by RNAome sequencing.
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Derks KW, Misovic B, van den Hout MC, Kockx CE, Gomez CP, Brouwer RW, Vrieling H, Hoeijmakers JH, van IJcken WF, and Pothof J
- Subjects
- Animals, Humans, Mice, High-Throughput Nucleotide Sequencing methods, RNA metabolism, Sequence Analysis, RNA methods, Transcriptome
- Abstract
Current RNA expression profiling methods rely on enrichment steps for specific RNA classes, thereby not detecting all RNA species in an unperturbed manner. We report strand-specific RNAome sequencing that determines expression of small and large RNAs from rRNA-depleted total RNA in a single sequence run. Since current analysis pipelines cannot reliably analyze small and large RNAs simultaneously, we developed TRAP, Total Rna Analysis Pipeline, a robust interface that is also compatible with existing RNA sequencing protocols. RNAome sequencing quantitatively preserved all RNA classes, allowing cross-class comparisons that facilitates the identification of relationships between different RNA classes. We demonstrate the strength of RNAome sequencing in mouse embryonic stem cells treated with cisplatin. MicroRNA and mRNA expression in RNAome sequencing significantly correlated between replicates and was in concordance with both existing RNA sequencing methods and gene expression arrays generated from the same samples. Moreover, RNAome sequencing also detected additional RNA classes such as enhancer RNAs, anti-sense RNAs, novel RNA species and numerous differentially expressed RNAs undetectable by other methods. At the level of complete RNA classes, RNAome sequencing also identified a specific global repression of the microRNA and microRNA isoform classes after cisplatin treatment whereas all other classes such as mRNAs were unchanged. These characteristics of RNAome sequencing will significantly improve expression analysis as well as studies on RNA biology not covered by existing methods.
- Published
- 2015
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38. A mRad51-GFP antimorphic allele affects homologous recombination and DNA damage sensitivity.
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Uringa EJ, Baldeyron C, Odijk H, Wassenaar E, van Cappellen WA, Maas A, Hoeijmakers JH, Baarends WM, Kanaar R, and Essers J
- Subjects
- Alleles, Animals, Cells, Cultured, DNA drug effects, DNA metabolism, DNA radiation effects, DNA Breaks, Double-Stranded, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Mice, Mitomycin pharmacology, Mutant Proteins genetics, Mutant Proteins metabolism, Rad51 Recombinase metabolism, Radiation, Ionizing, DNA Replication genetics, Heterozygote, Rad51 Recombinase genetics, Recombinational DNA Repair genetics
- Abstract
Accurate DNA double-strand break repair through homologous recombination is essential for preserving genome integrity. Disruption of the gene encoding RAD51, the protein that catalyzes DNA strand exchange during homologous recombination, results in lethality of mammalian cells. Proteins required for homologous recombination, also play an important role during DNA replication. To explore the role of RAD51 in DNA replication and DSB repair, we used a knock-in strategy to express a carboxy-terminal fusion of green fluorescent protein to mouse RAD51 (mRAD51-GFP) in mouse embryonic stem cells. Compared to wild-type cells, heterozygous mRad51(+/wt-GFP) embryonic stem cells showed increased sensitivity to DNA damage induced by ionizing radiation and mitomycin C. Moreover, gene targeting was found to be severely impaired in mRad51(+/wt-GFP) embryonic stem cells. Furthermore, we found that mRAD51-GFP foci were not stably associated with chromatin. From these experiments we conclude that this mRad51-GFP allele is an antimorphic allele. When this allele is present in a heterozygous condition over wild-type mRad51, embryonic stem cells are proficient in DNA replication but display defects in homologous recombination and DNA damage repair., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2015
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39. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.
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Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, and Campisi J
- Subjects
- Animals, Apoptosis, Cell Differentiation, Female, Fibroblasts metabolism, Luminescence, Male, Mice, Mice, Transgenic, Myofibroblasts metabolism, Platelet-Derived Growth Factor chemistry, Transgenes, Cellular Senescence, Endothelial Cells cytology, Mesoderm cytology, Platelet-Derived Growth Factor metabolism, Wound Healing
- Abstract
Cellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the physiological role(s) of the complex senescent phenotype, we generated a mouse model in which senescent cells can be visualized and eliminated in living animals. We show that senescent fibroblasts and endothelial cells appear very early in response to a cutaneous wound, where they accelerate wound closure by inducing myofibroblast differentiation through the secretion of platelet-derived growth factor AA (PDGF-AA). In two mouse models, topical treatment of senescence-free wounds with recombinant PDGF-AA rescued the delayed wound closure and lack of myofibroblast differentiation. These findings define a beneficial role for the SASP in tissue repair and help to explain why the SASP evolved., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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40. TTDA: big impact of a small protein.
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Theil AF, Hoeijmakers JH, and Vermeulen W
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- Animals, Humans, Mice, DNA Damage genetics, DNA Repair genetics, Transcription Factors genetics, Trichothiodystrophy Syndromes genetics
- Abstract
Nucleotide excision repair (NER) is a highly versatile DNA repair process which is able to remove a broad spectrum of structurally unrelated DNA helix-destabilizing lesions. The multi-subunit transcription/repair factor IIH (TFIIH) is an important decision maker in NER, by opening the DNA double helix after the initial damage recognition and subsequently verifying the lesion. Inherited mutations in TFIIH subunits are associated with NER-deficiency and a perplexing clinical heterogeneity, ranging from cancer-prone Xeroderma Pigmentosum to the progeroid diseases Cockayne Syndrome and Trichothiodystrophy (TTD). Three different TFIIH coding genes are implicated in TTD: XPD, XPB and TTDA. The latter gene encodes for a small (71 amino-acid) subunit and appeared important for the stabilization of the entire TFIIH complex. Based on analyzing TTD group A patient derived cells it was initially thought that TTDA has only a NER-stimulating role. In this review we summarize recent data showing that full disruption of TTDA expression in a knock-out mouse-model completely inactivates NER. Surprisingly, next to being essential for NER, TTDA appeared to be required also for embryonic development, indicative for the big impact this small protein has on basal biological processes., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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41. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.
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Barnhoorn S, Uittenboogaard LM, Jaarsma D, Vermeij WP, Tresini M, Weymaere M, Menoni H, Brandt RM, de Waard MC, Botter SM, Sarker AH, Jaspers NG, van der Horst GT, Cooper PK, Hoeijmakers JH, and van der Pluijm I
- Subjects
- Animals, Brain pathology, Cachexia etiology, Cachexia genetics, Central Nervous System physiology, Central Nervous System physiopathology, DNA Repair genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Deficiency Diseases genetics, Disease Models, Animal, Endonucleases genetics, Endonucleases metabolism, Female, Liver pathology, Longevity genetics, Male, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Proteins genetics, Nuclear Proteins metabolism, Osteoporosis etiology, Osteoporosis genetics, Pregnancy, Transcription Factors genetics, Transcription Factors metabolism, Aging genetics, DNA-Binding Proteins deficiency, Deficiency Diseases etiology, Endonucleases deficiency, Nuclear Proteins deficiency, Transcription Factors deficiency
- Abstract
As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.
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- 2014
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42. Refining analyses of copy number variation identifies specific genes associated with developmental delay.
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Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P, Friend KL, Baker C, Buono S, Vissers LE, Schuurs-Hoeijmakers JH, Hoischen A, Pfundt R, Krumm N, Carvill GL, Li D, Amaral D, Brown N, Lockhart PJ, Scheffer IE, Alberti A, Shaw M, Pettinato R, Tervo R, de Leeuw N, Reijnders MR, Torchia BS, Peeters H, O'Roak BJ, Fichera M, Hehir-Kwa JY, Shendure J, Mefford HC, Haan E, Gécz J, de Vries BB, Romano C, and Eichler EE
- Subjects
- Base Sequence, Carrier Proteins genetics, Cell Cycle Proteins, Child, Chromosome Mapping, Co-Repressor Proteins, Comparative Genomic Hybridization, DNA-Binding Proteins, Female, Genetic Association Studies, Haploinsufficiency genetics, Humans, Intellectual Disability genetics, Male, Molecular Sequence Data, Nuclear Proteins genetics, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Autistic Disorder genetics, DNA Copy Number Variations, Developmental Disabilities genetics, Genetic Predisposition to Disease genetics
- Abstract
Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.
- Published
- 2014
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43. Functional ex vivo assay to select homologous recombination-deficient breast tumors for PARP inhibitor treatment.
- Author
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Naipal KA, Verkaik NS, Ameziane N, van Deurzen CH, Ter Brugge P, Meijers M, Sieuwerts AM, Martens JW, O'Connor MJ, Vrieling H, Hoeijmakers JH, Jonkers J, Kanaar R, de Winter JP, Vreeswijk MP, Jager A, and van Gent DC
- Subjects
- Animals, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Female, Fluorescent Antibody Technique, Genes, BRCA1, Genes, BRCA2, Humans, Mice, Poly(ADP-ribose) Polymerase Inhibitors, Xenograft Model Antitumor Assays, Biological Assay methods, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Homologous Recombination radiation effects, Rad51 Recombinase radiation effects
- Abstract
Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are promising targeted treatment options for hereditary breast tumors with a homologous recombination (HR) deficiency caused by BRCA1 or BRCA2 mutations. However, the functional consequence of BRCA gene mutations is not always known and tumors can be HR deficient for other reasons than BRCA gene mutations. Therefore, we aimed to develop a functional test to determine HR activity in tumor samples to facilitate selection of patients eligible for PARP inhibitor treatment., Experimental Design: We obtained 54 fresh primary breast tumor samples from patients undergoing surgery. We determined their HR capacity by studying the formation of ionizing radiation induced foci (IRIF) of the HR protein RAD51 after ex vivo irradiation of these organotypic breast tumor samples. Tumors showing impaired RAD51 IRIF formation were subjected to genetic and epigenetic analysis., Results: Five of 45 primary breast tumors with sufficient numbers of proliferating tumor cells were RAD51 IRIF formation deficient (11%, 95% CI, 5%-24%). This HR defect was significantly associated with triple-negative breast cancer (OR, 57; 95% CI, 3.9-825; P = 0.003). Two of five HR-deficient tumors were not caused by mutations in the BRCA genes, but by BRCA1 promoter hypermethylation., Conclusion: The functional RAD51 IRIF assay faithfully identifies HR-deficient tumors and has clear advantages over gene sequencing. It is a relatively easy assay that can be performed on biopsy material, making it a powerful tool to select patients with an HR-deficient cancer for PARP inhibitor treatment in the clinic., (©2014 American Association for Cancer Research.)
- Published
- 2014
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44. Priming of microglia in a DNA-repair deficient model of accelerated aging.
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Raj DD, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, Brouwer N, Meijer MM, de Waard MC, van der Pluijm I, Brandt R, Kreft KL, Laman JD, de Haan G, Biber KP, Hoeijmakers JH, Eggen BJ, and Boddeke HW
- Subjects
- Animals, Cytokines metabolism, DNA-Binding Proteins genetics, Disease Models, Animal, Endonucleases genetics, Lipopolysaccharides, Mice, Mutant Strains, Mutation, Phagocytosis, Prosencephalon pathology, Aging pathology, Aging, Premature genetics, Aging, Premature pathology, DNA Repair-Deficiency Disorders genetics, DNA Repair-Deficiency Disorders pathology, Inflammation pathology, Microglia pathology
- Abstract
Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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45. Pollitt syndrome patients carry mutation in TTDN1.
- Author
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Swagemakers SM, Jaspers NG, Raams A, Heijsman D, Vermeulen W, Troelstra C, Kremer A, Lincoln SE, Tearle R, Hoeijmakers JH, and van der Spek PJ
- Abstract
Complete human genome sequencing was used to identify the causative mutation in a family with Pollitt syndrome (MIM #275550), comprising two non-consanguineous parents and their two affected children. The patient's symptoms were reminiscent of the non-photosensitive form of recessively inherited trichothiodystrophy (TTD). A mutation in the TTDN1/C7orf11 gene, a gene that is known to be involved in non-photosensitive TTD, had been excluded by others by Sanger sequencing. Unexpectedly, we did find a homozygous single-base pair deletion in the coding region of this gene, a mutation that is known to cause non-photosensitive TTD. The deleterious variant causing a frame shift at amino acid 93 (C326delA) followed the right mode of inheritance in the family and was independently validated using conventional DNA sequencing. We expect this novel DNA sequencing technology to help redefine phenotypic and genomic variation in patients with (mono) genetic disorders in an unprecedented manner.
- Published
- 2014
- Full Text
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46. Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1.
- Author
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Siemiatkowska AM, Schuurs-Hoeijmakers JH, Bosch DG, Boonstra FN, Riemslag FC, Ruiter M, de Vries BB, den Hollander AI, Collin RW, and Cremers FP
- Subjects
- Humans, Leber Congenital Amaurosis genetics, Mutation, Nicotinamide-Nucleotide Adenylyltransferase genetics
- Abstract
Importance: The NMNAT1 gene was recently found to be mutated in a subset of patients with Leber congenital amaurosis and macular atrophy. The most prevalent NMNAT1 variant was p.Glu257Lys, which was observed in 38 of 106 alleles (35.8%). On the basis of functional assays, it was deemed a severe variant., Observations: The p.Glu257Lys variant was 80-fold less frequent in a homozygous state in patients with Leber congenital amaurosis than predicted based on its heterozygosity frequency in the European American population. Moreover, we identified this variant in a homozygous state in a patient with no ocular abnormalities., Conclusions and Relevance: On the basis of these results, the p.Glu257Lys variant is considered not fully penetrant. Homozygotes of the p.Glu257Lys variant in most persons are therefore not associated with ocular disease. Consequently, genetic counselors should exercise great caution in the interpretation of this variant.
- Published
- 2014
- Full Text
- View/download PDF
47. Disruptive CHD8 mutations define a subtype of autism early in development.
- Author
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Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LELM, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O'Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BBA, Katsanis N, and Eichler EE
- Subjects
- Adolescent, Amino Acid Sequence, Animals, Brain growth & development, Brain pathology, Child, Child Development Disorders, Pervasive classification, Child Development Disorders, Pervasive pathology, Child, Preschool, DNA-Binding Proteins metabolism, Female, Gastrointestinal Tract innervation, Gastrointestinal Tract physiopathology, Humans, Macaca mulatta, Male, Megalencephaly pathology, Molecular Sequence Data, Mutation, Sequence Alignment, Transcription Factors metabolism, Zebrafish, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, Child Development Disorders, Pervasive genetics, Child Development Disorders, Pervasive physiopathology, DNA-Binding Proteins genetics, Transcription Factors genetics
- Abstract
Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
48. The DNA damage response: the omics era and its impact.
- Author
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Derks KW, Hoeijmakers JH, and Pothof J
- Subjects
- Aging pathology, Genomics, Humans, Neoplasms pathology, Proteomics, Signal Transduction genetics, Aging genetics, DNA Damage genetics, High-Throughput Nucleotide Sequencing methods, Neoplasms genetics
- Abstract
The emergence of high density technologies monitoring the genome, transcriptome and proteome in relation to genotoxic stress have tremendously enhanced our knowledge on global responses and dynamics in the DNA damage response, including its relation with cancer and aging. Moreover, '-omics' technologies identified many novel factors, their post-translational modifications, pathways and global responses in the cellular response to DNA damage. Based on omics, it is currently estimated that thousands of gene(product)s participate in the DNA damage response, recognizing complex networks that determine cell fate after damage to the most precious cellular molecule, DNA. The development of next generation sequencing technology and associated specialized protocols can quantitatively monitor RNA and DNA at unprecedented single nucleotide resolution. In this review we will discuss the contribution of omics technologies and in particular next generation sequencing to our understanding of the DNA damage response and the future prospective of next generation sequencing, its single cell application and omics dataset integration in unraveling intricate DNA damage signaling networks., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
49. Understanding nucleotide excision repair and its roles in cancer and ageing.
- Author
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Marteijn JA, Lans H, Vermeulen W, and Hoeijmakers JH
- Subjects
- DNA Damage, DNA Repair genetics, Humans, Models, Biological, Ubiquitin physiology, Aging genetics, DNA Repair physiology, Neoplasms genetics
- Abstract
Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype-phenotype correlations of transcription-coupled repair disorders.
- Published
- 2014
- Full Text
- View/download PDF
50. Preoperative fasting protects against renal ischemia-reperfusion injury in aged and overweight mice.
- Author
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Jongbloed F, de Bruin RW, Pennings JL, Payán-Gómez C, van den Engel S, van Oostrom CT, de Bruin A, Hoeijmakers JH, van Steeg H, IJzermans JN, and Dollé ME
- Subjects
- Age Factors, Animals, Blood Urea Nitrogen, Female, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Overweight, Oxidative Stress, Fasting, Kidney pathology, Kidney Transplantation adverse effects, Reperfusion Injury prevention & control
- Abstract
Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice. Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice. Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. A mRNA analysis indicated the involvement of metabolic processes including fatty acid oxidation and retinol metabolism, and the NRF2-mediated stress response. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well.
- Published
- 2014
- Full Text
- View/download PDF
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