Heidi Rossmann

Johannes Gutenberg-Universität Mainz, Mayence, Rheinland-Pfalz, Germany

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Publications (71)412.77 Total impact

  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555285 · 1.67 Impact Factor
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    ABSTRACT: Context: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndromes type 1-4 and are associated with multiple and recurrent pheochromocytomas (Pheo) and PGLs. SDHC mutations most frequently result in benign, non-functional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date. Objectives: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue. Design: In three unrelated patients referred for routine genetic testing SDHB, SDHC, and SDHD genes were sequenced and gross deletions were excluded by MLPA (MRC Holland). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry. Results: In a patient with a non-functioning thoracic PGL metastatic to the bone, the lungs and mediastinal lymph nodes we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics but both showed benign HNPGLs. Conclusions We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL even though malignancy is probably rare.
    The Journal of Clinical Endocrinology and Metabolism 12/2014; 99(3):jc20133486. DOI:10.1210/jc.2013-3486 · 6.31 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2014; 122(03). DOI:10.1055/s-0034-1372114 · 1.76 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2014; 122(03). DOI:10.1055/s-0034-1372078 · 1.76 Impact Factor
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    ABSTRACT: Clinical and experimental evidence suggests a protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx-1) in the atherogenic process. GPx-1 deficiency accelerates atherosclerosis and increases lesion cellularity in ApoE(-/-) mice. However, the distribution of GPx-1 within the atherosclerotic lesion as well as the mechanisms leading to increased macrophage numbers in lesions is still unknown. Accordingly, the aims of the present study were (1) to analyze which cells express GPx-1 within atherosclerotic lesions and (2) to determine whether a lack of GPx-1 affects macrophage foam cell formation and cellular proliferation. Both in situ-hybridization and immunohistochemistry of lesions of the aortic sinus of ApoE(-/-) mice after 12 weeks on a Western type diet revealed that both macrophages and - even though to a less extent - smooth muscle cells contribute to GPx-1 expression within atherosclerotic lesions. In isolated mouse peritoneal macrophages differentiated for 3 days with macrophage-colony-stimulating factor (MCSF), GPx-1 deficiency increased oxidized low density-lipoprotein (oxLDL) induced foam cell formation and led to increased proliferative activity of peritoneal macrophages. The MCSF- and oxLDL-induced proliferation of peritoneal macrophages from GPx-1(-/-)ApoE(-/-) mice was mediated by the p44/42 MAPK (p44/42 mitogen-activated protein kinase), namely ERK1/2 (extracellular-signal regulated kinase 1/2), signaling pathway as demonstrated by ERK1/2 signaling pathways inhibitors, Western blots on cell lysates with primary antibodies against total and phosphorylated ERK1/2, MEK1/2 (mitogen-activated protein kinase kinase 1/2), p90RSK (p90 ribosomal s6 kinase), p38 MAPK and SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), and immunohistochemistry of mice atherosclerotic lesions with antibodies against phosphorylated ERK1/2, MEK1/2 and p90RSK. Representative effects of GPx-1 deficiency on both macrophage proliferation and MAPK phosphorylation could be abolished by the GPx mimic ebselen. The present study demonstrates that GPx-1 deficiency has a significant impact on macrophage foam cell formation and proliferation via the p44/42 MAPK (ERK1/2) pathway encouraging further studies on new therapeutic strategies against atherosclerosis.
    PLoS ONE 08/2013; 8(8):e72063. DOI:10.1371/journal.pone.0072063 · 3.53 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2013; 121(03). DOI:10.1055/s-0033-1336672 · 1.76 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2013; 121(03). DOI:10.1055/s-0033-1336695 · 1.76 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2013; 121(03). DOI:10.1055/s-0033-1336654 · 1.76 Impact Factor
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    ABSTRACT: PURPOSE: Knowledge of the genetic backgrounds of hereditary syndromes, which are increasingly being characterized, enables genetic screening of family members of affected patients. Upon detection of a mutation, genetic counselling and clinical screening including imaging modalities and biochemical analyses are commonly performed. METHODS: Unaffected, mutation-positive relatives of index patients with hereditary paraganglioma syndromes were offered PET imaging with [(18)F]fluorodihydroxyphenylalanine and the incidence of pathological findings was retrospectively analysed in relation to mutations of the succinate dehydrogenase enzyme complex. PET only or PET/CT was performed in 21 individuals from eight families with SDHD, one family with SDHC and two families with SDHB mutations. Screening was offered every 2 to 5 years. RESULTS: Of the 21 individuals, 14 showed paraganglioma during screening. In particular, in only 2 of 15 patients with a SDHD mutation were the findings completely unremarkable on PET screening. However, false-negative lesions for abdominal manifestations in two SDHD-positive patients were detected. CONCLUSION: FDOPA PET is a sensitive imaging modality which should be offered to patients with a detected SDHx (SDHD) mutation, preferably using a hybrid technique.
    European Journal of Nuclear Medicine 02/2013; 40(6). DOI:10.1007/s00259-013-2346-6 · 5.22 Impact Factor
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    ABSTRACT: BACKGROUND: Dyslipidemia in Gaucher disease includes reduced total, low-density lipoprotein (LDL)-, and high-density lipoprotein (HDL)-cholesterol (C). No prospective analysis of lipid profile changes in treatment-naïve patients under enzyme replacement therapy (ERT) is available. METHODS: We analyzed lipid profile changes during ERT in a prospective controlled manner. Twelve treatment-naïve patients, Gaucher disease type 1 (GD1), 29.5 ± 12.9 years, 4M/8F. Diagnosis was made by enzymatic measurement and mutational analysis. Total-, LDL-, and HDL-C, triglycerides (TG), and LDL subfractions were assessed before the start of ERT with imiglucerase and biannually for 3 years. Patients were matched with healthy controls before and after 3 years of ERT. RESULTS: At baseline, we found severely reduced HDL-C concentrations (23.6 ± 5.4 mg/dl) and enhanced LDL/HDL ratios (3.1 ± 0.7). HDL-C increased after 6 months (29.2 ± 5.7, p = 0.023), LDL/HDL ratio decreased after 30 months (2.5 ± 0.5, p = 0.039). TG, even not consistently enhanced at baseline (128 ± 31.3 mg/dl), yet higher than in controls (p < 0.001), decreased after 18 months, being comparable with controls after 3 years of ERT. Small, dense LDL (mg/dl) increased continuously without significant difference to controls. After 3 years of ERT, only reduced HDL-C concentrations persisted as a potentially atherogenic alteration; however, mean concentrations markedly improved (42.9 ± 8.3 mg/dl, p < 0.001). Lipid parameters correlated with six markers of disease severity. CONCLUSIONS: This is the first prospective controlled study regarding lipid profile dynamics during ERT (glucocerebrosidase) in initially treatment-naïve GD1 patients. The most important changes were reduced HDL-C and enhanced LDL/HDL ratio. Their dynamics during ERT and correlations with markers of disease activity suggest that they can be considered markers of disease severity and follow-up in Gaucher patients under treatment.
    Journal of Inherited Metabolic Disease 09/2012; 36(3). DOI:10.1007/s10545-012-9529-3 · 4.14 Impact Factor
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    ABSTRACT: Attention of the otorhinolaryngologist needs to be drawn to the versatile aspects of head and neck paragangliomas (PGLs). This study is a retrospective, nonrandomized clinical study of all 175 individuals with PGLs treated in our department between 1989 and 2010. A genetic analysis was performed on 86 patients. The 175 patients presented 224 head and neck PGLs as well as 2 thyroid papillary carcinomas. Genetic analysis resulted in 1 patient positive for a von Hippel-Lindau (VHL) gene mutation and 34 for succinate dehydrogenase (SDH) gene mutations (22 SDHD, 7 SDHC, and 5 SDHB), 12 of the latter carrying a novel mutation. Thirty-three patients (18.9%) had multiple PGLs and 11 patients (6.3%) had a malignant paraganglioma. SDH-mutation carriers had multiple tumors in 64.7% and malignant paragangliomas in 20.6%. Multifocal occurrence, potential malignancy, genetic aspects, possible coincidence of thyroid carcinoma, and hormone production have to be considered in patients with head and neck PGLs.
    Head & Neck 05/2012; 34(5):632-7. DOI:10.1002/hed.21790 · 3.01 Impact Factor
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    ABSTRACT: Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg(689) (MSP(wt)) and Cys(689) (MSP(mut)) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP(mut) significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.
    Genes and immunity 01/2012; 13(4):321-7. DOI:10.1038/gene.2011.88 · 3.79 Impact Factor
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    ABSTRACT: One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.
    PLoS Genetics 12/2011; 7(12):e1002367. DOI:10.1371/journal.pgen.1002367 · 8.17 Impact Factor
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    ABSTRACT: Morbus Fabry is a hereditary metabolic disorder with low prevalence and late clinical manifestation. A defect in the α-galactosidase gene leads to lysosomal accumulation of the glycolipid globotriaosylceramide (Gb3). Gb3 may be used for monitoring of enzyme replacement therapy (ERT), but diagnostic sensitivity is limited. Recently, globotriaosylsphingosine (lysoGb3) was introduced as a promising new marker with significantly better sensitivity. For Fabry diagnosis, clinical studies and possible therapy monitoring, we established a fast and reliable LC-MS/MS assay for quantification of lysoGb3 in human plasma. Protein precipitation and glycolipid extraction from EDTA plasma was performed using acetone/methanol. Samples were analyzed by UPLC-MS/MS in MRM mode. In contrast to HPLC with fluorescence detection, the LC-MS/MS method requires no derivatization, less sample preparation and less instrument analysis time (<3 min). As internal standard (ISTD), a glycine derivative of lysoGb3 was synthesized, and the product was purified by HPLC. ISTD properties such as polarity (affecting extraction and elution), ionization and fragmentation pathway were almost identical compared to the analyte. The new LC-MS/MS assay for the Fabry marker lysoGb3 shows good performance and allowed for better discrimination between Fabry patients and controls than Gb3.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 11/2011; 883-884:128-35. DOI:10.1016/j.jchromb.2011.11.020 · 2.69 Impact Factor
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    ABSTRACT: Cerebral hypometabolism and abnormal levels of amyloid beta (Aβ), total (t-tau) and phosphorylated tau (ptau) proteins in cerebrospinal fluid (CSF) are established biomarkers of Alzheimer's disease (AD). We examined the agreement between these biomarkers in a single center study of patients with AD of severity extending over a wide range. Forty seven patients (MMSE 21.4 ± 3.6, range 13-28 points) with incipient and probable AD underwent positron emission tomography with [18F]-fluorodeoxyglucose (FDG-PET) and lumbar puncture for CSF assays of Aβ1-42, p-tau181, and t-tau. All findings were classified as either positive or negative for AD. Statistical analyses were performed for the whole sample (n=47) and for the subgroups stratified as mild (MMSE > 20 points, n=30) and moderate (MMSE < 21 points, n=17) AD. In the whole patient sample, the agreement with the FDG-PET finding was 77% (chance-corrected kappa [κ]=0.34, p=0.016) for t-tau, 68% (κ=0.10, n.s.) for p-tau181, and 68% (κ=0.04, n.s.) for Aβ1-42. No significant agreement was found in the mild AD subgroup, while there was a strong agreement for t-tau (94%, κ=0.77, p=0.001) and p-tau181 (88%, κ=0.60, p=0.014) in the moderate AD group. A significant agreement between the FDG-PET and CSF tau findings in patients with AD supports the view that both are markers of neurodegeneration. CSF tau proteins and FDG-PET might substitute each other as supportive diagnostic tools in patients with suspected moderate-to-severe Alzheimer's dementia, while this is not the case in subjects at an earlier disease stage.
    Current Alzheimer research 10/2011; 9(2):241-7. DOI:10.2174/156720512799361592 · 3.80 Impact Factor
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    ABSTRACT: Esophageal involvement in the context of opportunistic infections in human immunodeficiency virus (HIV) positive patients is a frequent phenomenon. However, worldwide esophageal achalasia has been described only twice in HIV-infected patients.We report the case of a 44-year-old Caucasian patient with HIV and Hepatitis C virus (HIV/HCV) coinfection who, within 2.5 years, displayed a progressive symptomatology with dysphagia, retrosternal pain, regurgitation as well as a considerable loss of weight before achalasia was finally diagnosed. Treatment was performed primarily surgically by means of laparoscopic Heller myotomy with an anterior 180° semifundoplication according to Dor.Histopathology of the specimens taken from the lower esophageal sphincter high-pressure zone proved alterations with abundant connective tissue and only scarce parts of the smooth muscular system without inflammatory infiltrations. In addition, the ganglia cells of the myenteric plexus as well as the interstitial cells of Cajal were significantly reduced. Interestingly, specific gene sequences of the hepatitis C virus could be detected in the esophageal tissue specimen. In contrast, analysis of specific HIV-gene sequences in the same tissue revealed a negative result.The possible but previously unknown relationship between esophageal achalasia and coinfection with HIV and HCV, also described as neurotropic viruses, will be discussed.
    Der Chirurg 07/2011; 82(11):1021-6. DOI:10.1007/s00104-011-2140-6 · 0.52 Impact Factor
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    ABSTRACT: NASH (non-alcoholic steatohepatitis) is considered the hepatic manifestation of the metabolic syndrome (MS). We aimed to analyze lipid, carbohydrate, and iron metabolism in NASH. 37 patients with MS (17 M/20 F, 51+/-15 years), elevated transaminases; 25 patients had histologically proven NASH (NAS score≥5), 12 patients had toxic background (nonNASH). 37 age, sex, BMI-matched healthy controls. Lipid variables, LDL-subfractions, iron, ferritin, transferrin (T), transferrin saturation (TS), and hepcidin (H) were measured in patients/controls. Oral glucose tolerance tests were performed. NASH patients with steatosis gr. 2 and 3 (>33% hepatic fat) had higher sd-LDL (mg/dl) concentrations than patients with steatosis gr. 1 (<33%) (p=0.002), nonNASH patients (p=0.03) and controls (p=0.001). Sd absolute (mg/dl) correlated directly with the steatosis grade only in patients with NASH and steatosis >33% (p=0.04). NASH-patients showed higher insulin, C-peptide and IRI values than nonNASH patients (p=0.034; 0.032; 0.04). H was increased in patients versus controls (p<0.001). H correlated with ferritin in MS-patients (p=0.01), correlated directly with sd-LDL (mg/dl) (p=0.017) and IRI (p<0.001) and indirectly with HDL (p=0.05) in NASH. No associations between hepatic inflammation/iron content on liver biopsy and variables of lipid metabolism were found but hepcidin correlated with hepatic inflammation in all patients and with NAS scores in NASH. NASH-patients show insulin resistance and increased sd-LDL subfractions, suggesting an atherogenic profile. The correlation of H with sd-LDL and IRI, without relation to hepatic iron content suggests a putative link between inflammation, carbohydrate and lipid metabolism in NASH.
    European Journal of Internal Medicine 06/2011; 22(3):305-10. DOI:10.1016/j.ejim.2011.01.011 · 2.30 Impact Factor
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    ABSTRACT: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)). The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
    Circulation Cardiovascular Genetics 05/2011; 4(4):403-12. DOI:10.1161/CIRCGENETICS.110.958728 · 5.34 Impact Factor
  • Atherosclerosis Supplements 06/2010; 11(2):99-99. DOI:10.1016/S1567-5688(10)70455-4 · 9.67 Impact Factor
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    ABSTRACT: Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself. This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.
    PLoS ONE 05/2010; 5(5):e10693. DOI:10.1371/journal.pone.0010693 · 3.53 Impact Factor

Publication Stats

1k Citations
412.77 Total Impact Points

Institutions

  • 2008–2013
    • Johannes Gutenberg-Universität Mainz
      • • Institute of Inorganic and Analytical Chemistry
      • • Institute for Nuclear Chemistry
      Mayence, Rheinland-Pfalz, Germany
  • 2011
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
      • Institute of Clinical Chemistry and Laboratory Medicine (Central Laboratory)
      Mainz, Rhineland-Palatinate, Germany
    • Universitätsklinikum Freiburg
      • Institute of Clinical Chemistry and Laboratory Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2005
    • Emory University
      • Division of Digestive Diseases
      Atlanta, Georgia, United States
  • 1998–2005
    • University of Tuebingen
      • • Department of Internal Medicine
      • • Eye Hospital
      Tübingen, Baden-Württemberg, Germany
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany
  • 2004
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 2003
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2001
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
  • 1995
    • Technische Universität München
      München, Bavaria, Germany