Annemarie Poustka

German Cancer Research Center, Heidelburg, Baden-Württemberg, Germany

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Publications (316)2255.89 Total impact

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    ABSTRACT: Research article Large scale statistical inference of signaling pathways from RNAi and microarray data
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    ABSTRACT: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
    Human Genetics 10/2011; 131(4):565-79. DOI:10.1007/s00439-011-1094-6 · 4.52 Impact Factor
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    ABSTRACT: Background: Autism spectrum disorder (ASD) has a strong genetic background with a higher frequency of affected males suggesting involvement of X-linked genes and possibly also other factors causing the unbalanced sex ratio in the etiology of the disorder. Syndrome pathogenesis is associated with abnormal brain development and manifests in several specific brain regions, especially cerebellum, amygdala and hippocampus. Positive linkage findings in genome wide screens and association studies identified susceptibility regions and genes on the X chromosome. Objectives: The ribosomal protein L10 gene (RPL10) located in Xq28 was identified as a candidate susceptibility gene for ASD through RNA in situ hybridization experiments. We detected high expression of RPL10 in mouse hippocampus. A first screen in 317 cases with autistic disorder, 21 cases with Asperger syndrome, and 7 cases with PDD-NOS representing 296 families revealed two missense mutations, L206M and H213Q, in two independent male-male affected sib-pair families (Klauck et al. 2006, Mol Psychiatry 11, 1073-84). In the follow-up study presented here, further 175 patients (145 autistic disorder, 27 Asperger syndrome, 3 PDD-NOS) representing 169 independent families have been screened to enlarge the study group. To understand the involvement of RPL10 in the pathogenesis of ASD, the RPL10 mRNA level in patients with ASD and controls was quantified. Methods: All seven exons of the RPL10 gene and the intronic snoRNA U70 have been screened by direct sequencing for mutations. RPL10 transcript levels were tested by quantitative RT-PCR on RNA extracted from lymphoblastoid cell lines (LCL) of different probands. Results: In the follow-up sample the H213Q mutation inherited from the carrier mother was identified in a male patient from a simplex family. The two different mutations, L206M and H213Q, are both located at the yet uncharacterized C-terminal end of the RPL10 protein, a constituent of the large ribosomal subunit. RPL10 itself is known to have impact on differential gene expression in yeast and man. Functional analyses in yeast revealed that both amino acid substitutions L206M and H213Q, respectively, confer hypomorphism with regard to the alteration of the translation process while keeping the basic translation functions intact. No statistical significant difference in RPL10 expression levels was found by testing 12 autistic patients including 2 patients from the two families carrying the H213Q mutation, 8 relatives of autistic patients and 7 controls. Moreover, the H213Q mutation has no effect on RPL10 expression in this cell system. Conclusions: The mutations identified may have a modulating effect on translation processes of synaptogenesis in neuronal development with impact especially on those cognitive functions that are mediated through the limbic system. Alterations due to the inherited mutation at the transcript level may be too subtle to be identified in the LCL system. In future, the functional impact of both mutations in its hemizygous state on the X chromosome will be further analyzed by in vitro and in vivo modeling.
    American Journal of Medical Genetics Part A 06/2011; 155A(6):1472-5. DOI:10.1002/ajmg.a.33977 · 2.05 Impact Factor
  • J Mollenhauer · A Poustka
    02/2011; DOI:10.4267/2042/38489
  • Encyclopedia of Cancer, 01/2011: pages 1117-1117; , ISBN: 978-3-642-16482-8
  • Chapter: Dendrimer
    Encyclopedia of Cancer, 01/2011: pages 1080-1080; , ISBN: 978-3-642-16482-8
  • Encyclopedia of Cancer, 01/2011: pages 1144-1144; , ISBN: 978-3-642-16482-8
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    ABSTRACT: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
    Human Molecular Genetics 10/2010; 19(20):4072-82. DOI:10.1093/hmg/ddq307 · 6.68 Impact Factor
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    ABSTRACT: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
    Nature 07/2010; 466(7304):368-72. DOI:10.1038/nature09146 · 42.35 Impact Factor
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    ABSTRACT: Despite recent progress in the identification of genetic and molecular alterations in prostate cancer, markers associated with tumor progression are scarce. Therefore precise diagnosis of patients and prognosis of the disease remain difficult. This study investigated novel molecular markers discriminating between low and highly aggressive types of prostate cancer. Using 52 microdissected cell populations of low- and high-risk prostate tumors, we identified via global cDNA microarrays analysis almost 1200 genes being differentially expressed among these groups. These genes were analyzed by statistical, pathway and gene enrichment methods. Twenty selected candidate genes were verified by quantitative real time PCR and immunohistochemistry. In concordance with the mRNA levels, two genes MAP3K5 and PDIA3 exposed differential protein expression. Functional characterization of PDIA3 revealed a pro-apoptotic role of this gene in PC3 prostate cancer cells. Our analyses provide deeper insights into the molecular changes occurring during prostate cancer progression. The genes MAP3K5 and PDIA3 are associated with malignant stages of prostate cancer and therefore provide novel potential biomarkers.
    Molecular Cancer 12/2009; 8:130. DOI:10.1186/1476-4598-8-130 · 5.40 Impact Factor
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    ABSTRACT: As a first step towards a more comprehensive functional characterization of cDNAs than bioinformatic analysis, which can only make functional predictions for about half of the cDNAs sequenced, we have developed and tested a strategy that allows their systematic and fast subcellular localization. We have used a novel cloning technology to rapidly generate N- and C-terminal green fluorescent protein fusions of cDNAs to examine the intracellular localizations of >100 expressed fusion proteins in living cells. The entire analysis is suitable for automation, which will be important for scaling up throughput. For >80% of these new proteins a clear intracellular localization to known structures or organelles could be determined. For the cDNAs where bioinformatic analyses were able to predict possible identities, the localization was able to support these predictions in 75% of cases. For those cDNAs where no homologies could be predicted, the localization data represent the first information.
    EMBO Reports 11/2009; DOI:10.1038/embor.2009.245 · 7.86 Impact Factor
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    ABSTRACT: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
    Nature 10/2009; 461(7265):802-808. DOI:10.1038/nature08490 · 42.35 Impact Factor
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    ABSTRACT: A detailed and quantitative analysis of disease-relevant signaling will greatly contribute to our understanding of tumorigenesis and cancer progression, and thus open new strategies for drug discovery. However, throughput and sensitivity of currently established methods available for proteome profiling do not comply with the needs of clinical research such as high sample capacity and low sample consumption. Protein microarrays emerged as a promising alternative to analyze the abundance of proteins and their phosphorylation status on a high-throughput level. Here we summarize recent methodological advancements in the field of reverse-phase protein arrays and demonstrate their potential for clinical research as well as for in vitro applications.
    PROTEOMICS - CLINICAL APPLICATIONS 10/2009; 3(10):1140-50. DOI:10.1002/prca.200780035 · 2.68 Impact Factor
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    ABSTRACT: Most malignant features of cancer cells are triggered by activated oncogenes and the loss of tumor suppressors due to mutation or epigenetic inactivation. It is still unclear, to what extend the escape of emerging cancer cells from recognition and elimination by the immune system is determined by similar mechanisms. We compared the transcriptomes of HCT116 colorectal cancer cells deficient in DNA methyltransferases (DNMTs) and of cells, in which the RAS pathway as the major growth-promoting signaling system is blocked by inhibition of MAPK. We identified the MHC Class I genes HLA-A1/A2 and the ULBP2 gene encoding 1 of the 8 known ligands of the activating NK receptor NKG2D among a cluster of immune genes up-regulated under the conditions of both DNMT-deficiency and MEK-inhibition. Bisulphite sequencing analyses of HCT116 with DNMT deficiency or after MEK-inhibition showed that de-methylation of the ULPB2 promoter correlated with its enhanced surface expression. The HLA-A promoters were not methylated indicating that components of the HLA assembly machinery were also suppressed in DNMT-deficient and MEK-inhibited cells. Increased HLA-A2 surface expression was correlated with enhanced recognition and lysis by A2-specific CTL. On the contrary, elevated ULBP2 expression was not reflected by enhanced recognition and lysis by NK cells. Cosuppression of HLA Class I and NKG2D ligands and genes encoding peptide transporters or proteasomal genes mediates a strong functional link between RAS activation, DNMT activity and disruption of the antigen presenting system controlling immune recognition in colorectal cancer cells.
    International Journal of Cancer 10/2009; 125(7):1626-39. DOI:10.1002/ijc.24557 · 5.01 Impact Factor
  • Blood Cells Molecules and Diseases 10/2009; 44(2):88. DOI:10.1016/j.bcmd.2009.10.005 · 2.33 Impact Factor
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    ABSTRACT: Making a definitive preoperative diagnosis in patients with indeterminate pulmonary nodules is still a challenge. Gene expression profiling may be a useful adjunctive diagnostic utility in this regard. We investigated the feasibility of bronchoscopic microsampling to collect endobronchial epithelial lining fluid to obtain RNA as a starting point for gene expression profiling. In 15 patients, epithelial lining fluid was collected in triplicate from subsegmental bronchi close to the pulmonary nodules and from contralateral lungs. Diagnosis was confirmed by transbronchial biopsy or surgery (non-small cell lung cancer, n = 11; benign or other lesions, n = 4). Total RNA was isolated from the samples and evaluated concerning quantity and quality. The complementary DNA was generated and analyzed by quantitative real-time polymerase chain reaction for potential lung cancer associated genes like matrix metalloprotinase (MMP9). Total RNA of adequate amount (>0.8 microg) and sufficient quality was obtained in 13 (86%) of the 15 patients. In patients with lung cancer, normalized MMP9 gene expression levels in endobronchial lining fluid samples collected close to the lesions were in median 12 times higher than levels in the matching contralateral samples. MMP9 expression levels were particularly high in endobronchial lining fluid samples collected from patients with squamous cell carcinoma but not elevated in the case of benign lesions. Our results show that quantitative gene expression analysis of endobronchial lining fluid collected by bronchoscopic microsampling is both feasible and reliable and may therefore be a useful additional diagnostic method in patients with indeterminate pulmonary nodules.
    The Journal of thoracic and cardiovascular surgery 09/2009; 138(2):474-9. DOI:10.1016/j.jtcvs.2009.04.024 · 3.99 Impact Factor
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    ABSTRACT: Autism and mental retardation (MR) show high rates of comorbidity and potentially share genetic risk factors. In this study, a rare approximately 2 Mb microdeletion involving chromosome band 15q13.3 was detected in a multiplex autism family. This genomic loss lies between distal break points of the Prader-Willi/Angelman syndrome locus and was first described in association with MR and epilepsy. Together with recent studies that have also implicated this genomic imbalance in schizophrenia, our data indicate that this CNV shows considerable phenotypic variability. Further studies should aim to characterise the precise phenotypic range of this CNV and may lead to the discovery of genetic or environmental modifiers.
    European journal of human genetics: EJHG 05/2009; 17(5):687-92. DOI:10.1038/ejhg.2008.228 · 4.23 Impact Factor
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    ABSTRACT: We describe a patient with autism and brachymetaphalangy, meeting criteria for 2q37 deletion syndrome (also called Albright Hereditary Osteodystrophy-like syndrome or Brachydactyly-Mental Retardation syndrome, OMIM 600430). Our molecular cytogenetic studies, including array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH), define the extent of the de novo deletion to a 3.5 Mb region on 2q37.3. Although a number of reports of patients with 2q37 deletion syndrome have been published, it remains unclear if gene expression and/or translation are altered by the deletion, thus contributing to the observed phenotypes. To address this question, we selected several candidate genes for the neuropsychiatric and skeletal anomalies found in this patient (autism and brachymetaphalangy). The deleted region in 2q37.3 includes the FERM, RhoGEF and pleckstrin domain protein 2 (FARP2), glypican 1 (GPC1), vigilin (HDLBP), kinesin family member 1A (KIF1A) and proline-alanine-rich STE20-related kinase (PASK), all of which are involved in skeletal or neural differentiation processes. Expression analyses of these genes were performed using RNA from lymphoblastoid cell lines of the patient and his family members. Here we demonstrate that three of these genes, FARP2, HDLBP, and PASK, are considerably downregulated in the patient's cell line. We hypothesize that haploinsufficiency of these genes may have contributed to the patient's clinical phenotype.
    American Journal of Medical Genetics Part A 05/2009; 149A(5):952-9. DOI:10.1002/ajmg.a.32779 · 2.05 Impact Factor
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    ABSTRACT: Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappaB activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function in mucosal protection and of its broad pathogen-binding specificity. We report that DMBT1 directly interacts with dextran sulfate sodium (DSS) and carrageenan, a structurally similar sulfated polysaccharide, which is used as a texturizer and thickener in human dietary products. However, binding of DMBT1 does not reduce the cytotoxic effects of these agents to intestinal epithelial cells in vitro. DSS and carrageenan compete for DMBT1-mediated bacterial aggregation via interaction with its bacterial-recognition motif. Competition and ELISA studies identify poly-sulfated and poly-phosphorylated structures as ligands for this recognition motif, such as heparansulfate, LPS, and lipoteichoic acid. Dose-response studies in Dmbt1(-/-) and Dmbt1(+/+) mice utilizing the DSS-induced colitis model demonstrate a differential response only to low but not to high DSS doses. We propose that DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-kappaB activation.
    European Journal of Immunology 03/2009; 39(3):833-42. DOI:10.1002/eji.200838689 · 4.52 Impact Factor
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    ABSTRACT: Anorectal melanoma (AM) forms a rare but highly malignant subset of mucosal melanoma with an extremely poor prognosis. Although AMs display histological and immunohistochemical features very similar to cutaneous melanoma (CM), no association exists either with exposure to ultraviolet light or with melanocytic naevi. While AMs are clearly distinguished from CM by displaying few BRAF mutations, they are commonly indistinguishable from CM at the level of gene expression. The aim was to carry out expression analyses of classical immunohistochemical markers and of the protein deleted in malignant brain tumours 1 (DMBT1) in cases of primary anorectal malignant melanoma and CM. Expression analyses of classical immunohistochemical markers (S100, HMB45, Melan A and MiTF) and of the protein DMBT1 were carried out in 27 cases of primary anorectal malignant melanoma and 26 cases of CM. All AM cases analysed showed expression of at least three of the classical markers for melanoma. However, immunohistochemistry showed 19 out of 27 AM to be positive for DMBT1, which represented a statistically significant difference (P = 0.0009) compared with CM (six out of 26), which more commonly are negative for DMBT1 expression. These results identify DMBT1 as a molecular feature that may allow distinction between AM and CM and support the notion that AM represents an entity molecularly distinct from CM.
    Histopathology 02/2009; 54(2):233-40. DOI:10.1111/j.1365-2559.2008.03200.x · 3.30 Impact Factor

Publication Stats

22k Citations
2,255.89 Total Impact Points


  • 2000–2011
    • German Cancer Research Center
      • Division of Molecular Genome Analysis
      Heidelburg, Baden-Württemberg, Germany
    • University of Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2008
    • Johns Hopkins University
      • Division of Cardiology
      Baltimore, Maryland, United States
  • 2007
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2005
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2004
    • Universität Heidelberg
      • Institute of Medical Biometry and Informatics
      Heidelburg, Baden-Württemberg, Germany
  • 2002
    • Academisch Centrum Tandheelkunde Amsterdam
      • Field of Oral Biochemistry
      Amsterdam, North Holland, Netherlands
    • Humboldt-Universität zu Berlin
      • Department of Biology
      Berlín, Berlin, Germany
  • 1999
    • University of Reading
      • Department of Animal Science
      Reading, England, United Kingdom
    • Institute for Child Health Policy (ICHP)
      اورموند بيتش، فلوريدا, Florida, United States
  • 1996–1999
    • Max Planck Institute for Molecular Genetics
      Berlín, Berlin, Germany
  • 1997
    • The Ohio State University
      • Department of Pediatrics
      Columbus, Ohio, United States
  • 1995
    • Uppsala University Hospital
      Uppsala, Uppsala, Sweden
  • 1991
    • Emory University
      Atlanta, Georgia, United States
  • 1990
    • Massachusetts General Hospital
      • Neuroepigenetics Laboratory
      Boston, Massachusetts, United States
    • Boston Children's Hospital
      • Division of Genetics
      Boston, Massachusetts, United States
    • Erasmus Universiteit Rotterdam
      • Department of Cell Biology
      Rotterdam, South Holland, Netherlands
  • 1983–1988
    • European Molecular Biology Laboratory
      Heidelburg, Baden-Württemberg, Germany