Barbara Kloeckener-Gruissem
University of Zurich
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Featured researches published by Barbara Kloeckener-Gruissem.
Progress in Retinal and Eye Research | 2010
Wolfgang Berger; Barbara Kloeckener-Gruissem; John Neidhardt
During the last two to three decades, a large body of work has revealed the molecular basis of many human disorders, including retinal and vitreoretinal degenerations and dysfunctions. Although belonging to the group of orphan diseases, they affect probably more than two million people worldwide. Most excitingly, treatment of a particular form of congenital retinal degeneration is now possible. A major advantage for treatment is the unique structure and accessibility of the eye and its different components, including the vitreous and retina. Knowledge of the many different eye diseases affecting retinal structure and function (night and colour blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic development. We have attempted to present a comprehensive picture of these disorders, including biological, clinical, genetic and molecular information. The structural organization of the review leads the reader through non-syndromic and syndromic forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more than 165 genes. Clinical variability and genetic heterogeneity have an important impact on genetic testing and counselling of affected families. As phenotypes do not always correlate with the respective genotypes, it is of utmost importance that clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers understand the relationships between phenotypic manifestations and specific genes, as well as mutations and pathophysiologic mechanisms. We discuss future perspectives.
American Journal of Human Genetics | 2006
Christina Zeitz; Barbara Kloeckener-Gruissem; Ursula Forster; Susanne Kohl; Bernd Wissinger; Gabor Matyas; François-Xavier Borruat; Daniel F. Schorderet; Eberhart Zrenner; Francis L. Munier; Wolfgang Berger
Mutations in genes encoding either components of the phototransduction cascade or proteins presumably involved in signaling from photoreceptors to adjacent second-order neurons have been shown to cause congenital stationary night blindness (CSNB). Sequence alterations in CACNA1F lead to the incomplete type of CSNB (CSNB2), which can be distinguished by standard electroretinography (ERG). CSNB2 is associated with a reduced rod b-wave, a substantially reduced cone a-wave, and a reduced 30-Hz flicker ERG response. CACNA1F encodes the alpha 1-subunit of an L-type Ca2+ channel (Cav1.4 alpha ), which is specific to photoreceptors and is present at high density in the synaptic terminals. Ten of our patients with CSNB2 showed no mutation in CACNA1F. To identify the disease-causing mutations, we used a candidate-gene approach. CABP4, a member of the calcium-binding protein (CABP) family, is located in photoreceptor synaptic terminals and is directly associated with the C-terminal domain of the Cav1.4 alpha . Mice lacking either Cabp4 or Cav1.4 alpha display a CSNB2-like phenotype. Here, we report for the first time that mutations in CABP4 lead to autosomal recessive CSNB. Our studies revealed homozygous and compound heterozygous mutations in two families. We also show that these mutations reduce the transcript levels to 30%-40% of those in controls. This suggests that the reduced amount of CABP4 is the reason for the signaling defect in these patients.
European Journal of Immunology | 2007
Sonja Junge; Barbara Kloeckener-Gruissem; Romain Zufferey; Andre Keisker; Bettina Salgo; Jean-Claude Fauchère; Franziska Scherer; Tarek Shalaby; Michael A. Grotzer; Ulrich Siler; Reinhard Seger; Tayfun Güngör
CD31+CD45RA+RO– lymphocytes contain high numbers of T cell receptor circle (TREC)‐bearing T cells; however, the correlation between CD31+CD4+ lymphocytes and TREC during aging and under lymphopenic conditions has not yet been sufficiently investigated. We analyzed TREC, telomere length and telomerase activity within sorted CD31+ and CD31– CD4+ lymphocytes in healthy individuals from birth to old age. Sorted CD31+CD45RA+RO– naive CD4+ lymphocytes contained high TREC numbers, whereas CD31+CD45RA–RO+ cells (comprising ⩽5% of CD4+ cells during aging) did not contain TREC. CD31+ overall CD4+ cells remained TREC rich despite an age‐related tenfold reduction from neonatal (100 : 1000) to old age (10 : 1000). Besides a high TREC content, CD31+CD45RA+RO–CD4+ cells exhibited significantly longer telomeres and higher telomerase activity than CD31–CD45RA+RO–CD4+ cells, suggesting that CD31+CD45RA+RO–CD4+ cells represent a distinct population of naive T cells with particularly low replicative history. To analyze the value of CD31 in lymphopenic conditions, we investigated six children after allogeneic hematopoietic stem cell transplantation (HSCT). Reemerging overall CD4+ as well as naive CD45RA+RO–CD4+ cells predominantly expressed CD31 and correlated well with the recurrence of TREC 5–12 months after HSCT. Irrespective of limitations in the elderly, CD31 is an appropriate marker to monitor TREC‐rich lymphocytes essentially in lymphopenic children after HSCT.
Investigative Ophthalmology & Visual Science | 2011
Barbara Kloeckener-Gruissem; Daniel Barthelmes; Stephan Labs; Christian Schindler; Malaika M. Kurz-Levin; Stephan Michels; Johannes Fleischhauer; Wolfgang Berger; Florian K. P. Sutter; Moreno Menghini
PURPOSE Neovascular age-related macular degeneration (AMD) resulting in decreased central vision severely impairs affected individuals. Current standard treatment is an intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Genetic factors that influence AMD and that affect the outcome of ranibizumab treatment were sought within a sample of Swiss patients. METHODS Changes in visual acuity (VA) after initiation of anti-VEGF treatment were observed during 12 months, and percentiles of VA were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2, and VEGFA) as well as not yet reported AMD-associated genes (KDR, LRP5, and FZD4) were determined, and their frequencies were compared. RESULTS Of the 309 eyes included in the study, 243 completed VA assessment. On average, 3.9 ±2.6 ranibizumab injections were administered. Based on the change in visual acuity, two responder groups were established: 63 eyes were assigned to the poor responders (≤25th percentile) and 63 eyes to the good responders (≥75th percentile). Individuals with genotype CC of p.Y402H in CFH had a decreased chance of positive treatment outcome compared with those with the CT and TT genotypes (P = 0.005 and P = 0.006). In this study, the genotype combination of AG at CFH with CT at FZD4 (SNP rs10898563) promised an increased chance of positive treatment outcome (P = 0.004). Furthermore, the association with the known genetic susceptibility loci CFH, HTRA1, and AMRS2 were confirmed, and a risk-conferring polymorphism in one new locus, LRP5, was identified. CONCLUSIONS Genetic predisposition may account for the variability in response to anti-VEGF treatment.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2006
David J. Kurz; Barbara Kloeckener-Gruissem; Alexander Akhmedov; Franz R. Eberli; Ines Bühler; Wolfgang Berger; Osmund Bertel; Thomas F. Lüscher
Objective—The mechanisms responsible for the age-related increase in the incidence of calcific aortic valve stenosis (CAS) are unclear but may include telomere-driven cellular senescence. Because telomere length varies widely among individuals of the same age, we hypothesized that patients with shorter telomeres would be prone to develop CAS late in life. Methods and Results—Mean telomere length was measured in leukocytes from a cohort of 193 patients ≥70 years of age with and without CAS. Pilot experiments performed in 30 patients with CAS and controls pair-matched for age, sex, and presence or absence of coronary disease demonstrated significantly shorter telomeres in the CAS group both by Southern blot hybridization (5.75±0.55 kbp versus 6.27±0.7 kbp, P=0.0023) and by a quantitative polymerase chain reaction-based technique (relative telomere length 0.88±0.19 versus 1.0±0.19, P=0.01). This finding was then confirmed in the whole cohort (CAS n=64, controls n=129, relative telomere length=0.86±0.16 versus 0.94±0.12, P=0.0003). Both groups were comparable for potential confounding characteristics. Subgroup analysis according to the presence or absence of coronary disease demonstrated no association of this disorder with telomere length. Conclusions—In the elderly, calcific aortic stenosis, but not coronary disease, is associated with shorter leukocyte telomere length.
European Journal of Human Genetics | 2013
Corry Weemaes; Maarten J. D. van Tol; Jun Wang; Monique M. van Ostaijen-ten Dam; Marja van Eggermond; Peter E. Thijssen; Caner Aytekin; Nicola Brunetti-Pierri; Mirjam van der Burg; E. Graham Davies; Alina Ferster; Dieter Furthner; Giorgio Gimelli; Andrew R. Gennery; Barbara Kloeckener-Gruissem; Stephan Meyn; Cynthia Powell; Ismail Reisli; Catharina Schuetz; Ansgar Schulz; Andrea Shugar; Peter J. van den Elsen; Silvère M. van der Maarel
Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.
American Journal of Human Genetics | 2008
Barbara Kloeckener-Gruissem; Kristof Vandekerckhove; Gudrun Nürnberg; John Neidhardt; Christina Zeitz; Peter Nürnberg; Isaak Schipper; Wolfgang Berger
Unobstructed vision requires a particular refractive index of the lens, a measure based on the organization of the structural proteins within the differentiated lens cells. To ensure an intact lens structure, homeostasis within the lens cells is indispensable. Alterations of the lens structure result in opacity and lead to cataract. Renal glucosuria is defined by elevated glucose level in the urine without hyperglycemia and without evidence of morphological renal anomalies. In a Swiss family with autosomal dominant juvenile cataract, microcornea, and renal glucosuria, we have identified a nonsense mutation in a member of the carboxylic acid transporter family SLC16. The underlying gene defect in SLC16A12 resides within a 3 cM region on chromosome 10q23.13 defined by linkage mapping of this phenotype. We found tissue-specific variability of SLC16A12 transcript levels in control samples, with high expression in the eye and kidney, the two organs affected by this syndrome. This report demonstrates biological relevance of this solute carrier. We hypothesize that SLC16A12 is important for lens and kidney homeostasis and discuss its potential role in age-related cataract.
Investigative Ophthalmology & Visual Science | 2008
Christina Zeitz; Alecia K. Gross; Dorothee Leifert; Barbara Kloeckener-Gruissem; Suzanne D. McAlear; Johannes R. Lemke; John Neidhardt; Wolfgang Berger
PURPOSE Mutations in RHO, PDE6B, and GNAT1 can lead to autosomal dominant congenital stationary night blindness (adCSNB). The study was conducted to identify the genetic defect in a large Swiss family affected with adCSNB and to investigate the pathogenic mechanism of the mutation. METHODS Two affected cousins of a large Swiss family were examined clinically by standard methods: funduscopy, EOG, ERG, and dark adaptometry. Twelve family members were screened for mutations in RHO. The ability of mutant rhodopsin to activate transducin constitutively was monitored by measuring the catalytic exchange of bound GDP for radiolabeled [(35)S]GTPgammaS in transducin. RESULTS A novel mutation was identified in RHO (c.884C>T, p.Ala295Val) in patients with adCSNB. They had full vision under photopic conditions, showed no fundus abnormalities, revealed EOG results in the normal range, but presented night blindness with an altered scotopic ERG. In the presence of 11-cis retinal, the mutant rhodopsin is inactive, similar to wild-type, responding only when exposed to light. However, in the absence of 11-cis-retinal, unlike wild-type opsin, the mutant opsin constitutively activates transducin. CONCLUSIONS The study adds a fourth rhodopsin mutation associated with CSNB. Although the phenotype of autosomal dominant CSNB may vary slightly in patients showing mutations in RHO, PDE6B, or GNAT1, the disease course seems to be stationary with only scotopic vision being affected. The data indicate that the mutant opsin activates transducin constitutively, which is a consistent and common feature of all four CSNB-associated rhodopsin mutations reported to date.
Nature Communications | 2015
Peter E. Thijssen; Yuya Ito; Giacomo Grillo; Jun Wang; Guillaume Velasco; Hirohisa Nitta; Motoko Unoki; Minako Yoshihara; Mikita Suyama; Yu Sun; Richard J.L.F. Lemmers; Jessica C. de Greef; Andrew Gennery; Paolo Picco; Barbara Kloeckener-Gruissem; Tayfun Güngör; Ismail Reisli; Capucine Picard; Kamila Kebaili; Bertrand Roquelaure; Tsuyako Iwai; Ikuko Kondo; Takeo Kubota; Monique M. van Ostaijen-ten Dam; Maarten J. D. van Tol; Corry Weemaes; Claire Francastel; Silvère M. van der Maarel; Hiroyuki Sasaki
The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.
PLOS ONE | 2012
Moreno Menghini; Barbara Kloeckener-Gruissem; Johannes Fleischhauer; Malaika M. Kurz-Levin; Florian K. P. Sutter; Wolfgang Berger; Daniel Barthelmes
Objective Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome. Methods Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr). Results 204 eyes were included. A change of +5.0 [−1;+11] letters and +1.5 [−5.5;+9.5] was observed with a median of 4 [3]; [7] and 10 [7]; [14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01). Conclusions Our data suggest that clinical decisions regarding treatment may be guided by observing patients’ initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value.