Institution
University of Kiel
Education•Kiel, Germany•
About: University of Kiel is a education organization based out in Kiel, Germany. It is known for research contribution in the topics: Population & Crystal structure. The organization has 27816 authors who have published 57114 publications receiving 2061802 citations. The organization is also known as: Christian Albrechts University & Christian-Albrechts-Universität zu Kiel.
Topics: Population, Crystal structure, Transplantation, Gene, Receptor
Papers published on a yearly basis
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TL;DR: It is shown that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary ciliaof renal epithelial cells in the pathogenesis of SLSN.
Abstract: Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children(1-3). Identification of four genes mutated in NPHP subtypes 1- 4 (refs. 4- 9) has linked the pathogenesis of NPHP to ciliary functions(9). Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.
377 citations
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Boston Children's Hospital1, University of Southern Denmark2, University of Tübingen3, University of Pavia4, University of Copenhagen5, Lyon College6, French Institute of Health and Medical Research7, HCL Technologies8, Aix-Marseille University9, University of Paris10, Paris Diderot University11, University of Hamburg12, Utrecht University13, Erasmus University Medical Center14, Mayo Clinic15, University of Genoa16, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico17, University of Michigan18, Université libre de Bruxelles19, University of Kiel20, Detmold21, Aarhus University Hospital22, University Hospital Heidelberg23, University of Tartu24, University of Colorado Denver25, Centre Hospitalier de Luxembourg26, Cairo University27, Ghent University Hospital28, Katholieke Universiteit Leuven29, University of Antwerp30, Leipzig University31, Children's Hospital of Philadelphia32
TL;DR: Clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy, and suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function.
Abstract: Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells—together with data from the literature—suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
377 citations
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McGill University1, McGill University Health Centre2, Children's Hospital of Eastern Ontario3, University of Kentucky4, National and Kapodistrian University of Athens5, Wake Forest University6, Princess Margaret Cancer Centre7, Indiana University8, Duke University9, University of Cambridge10, University of Kiel11, University of Western Australia12, Belfast City Hospital13, University Health Network14, University of Münster15
TL;DR: Findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches, and at least one germline or somatic deleterious SMarCA4 mutation in 30 of 32 cases.
Abstract: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.
376 citations
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TL;DR: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases, as well as single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
Abstract: IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
376 citations
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TL;DR: It is suggested that dipeptidyl peptidase IV might be involved in the degradation of neuropeptide Y and peptide YY to N-terminal truncated neuropeptic Y(3-36) and peptides YY and inactivates them for binding to one receptor subtype.
375 citations
Authors
Showing all 28103 results
Name | H-index | Papers | Citations |
---|---|---|---|
Stefan Schreiber | 178 | 1233 | 138528 |
Jun Wang | 166 | 1093 | 141621 |
William J. Sandborn | 162 | 1317 | 108564 |
Jens Nielsen | 149 | 1752 | 104005 |
Tak W. Mak | 148 | 807 | 94871 |
Annette Peters | 138 | 1114 | 101640 |
Severine Vermeire | 134 | 1086 | 76352 |
Peter M. Rothwell | 134 | 779 | 67382 |
Dusan Bruncko | 132 | 1042 | 84709 |
Gideon Bella | 129 | 1301 | 87905 |
Dirk Schadendorf | 127 | 1017 | 105777 |
Neal L. Benowitz | 126 | 792 | 60658 |
Thomas Schwarz | 123 | 701 | 54560 |
Meletios A. Dimopoulos | 122 | 1371 | 71871 |
Christian Weber | 122 | 776 | 53842 |