98 results on '"Hergersberg M"'
Search Results
2. Mutation hotspots in the human porphobilinogen deaminase gene: Recurrent mutations G111R and R173Q occurring at CpG motifs
- Author
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Schneider-Yin, X., Hergersberg, M., Schuurmans, M. M., Gregor, A., and Minder, E. I.
- Published
- 2004
- Full Text
- View/download PDF
3. A new mutation, 3905insT, accounts for 4.8% of 1173 CF chromosomes in Switzerland and causes a severe phenotype
- Author
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Hergersberg, M., Balakrishnan, Jaya, Bettecken, Thomas, Chevalier-Porst, Francoise, Brägger, Christian, Burger, René, Einschenk, Inge, Liechti-Gallati, Sabina, Morris, Michael, Schorderet, Daniel, Thonney, Francine, Moser, Hans, and Malik, Naseem
- Published
- 1997
- Full Text
- View/download PDF
4. Age at diagnosis and loss of heterozygosity on chromosome 1p and 19q in oligodendroglial tumors
- Author
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Hergersberg, M., Mariani, L., Vassella, E., Murtin, C., Weis, J., Moschopulos, M., Laeng, H., Landolt, H., Huber, A., and Roelcke, U.
- Published
- 2006
- Full Text
- View/download PDF
5. Biological aspects of cytosine methylation in eukaryotic cells
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Hergersberg, M.
- Published
- 1991
- Full Text
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6. Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred - a possible new syndrome
- Author
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Schmidt, H, Rudolph, G, Hergersberg, M, Schneider, K, Moradi, S, and Meitinger, T
- Published
- 2001
7. Tissue-specific expression of a FMR1/β-galactosidase fusion gene in transgenic mice
- Author
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Hergersberg, M., Matsuo, K., Gassmann, M., Schaffner, W., Luscher, B., Rulicke, T., and Adriano Aguzzi
- Abstract
Fragile X syndrome is one of the most common genetic causes of mental retardation, yet the mechanisms controlling expression of the fragile X mental retardation gene FMR1 are poorly understood. To identify sequences regulating FMR1 transcription, transgenic mouse lines were established using a fusion gene consisting of an E.coli β-galactosidase reporter gene (lacZ) linked to a 2.8 kb fragment spanning the 5′-region of FMR1. Five transgenic mouse lines showed lacZ expression in brain, in particular in neurons of the hippocampus and the granular layer of the cerebellum. Expression of the reporter gene was also detected in Leydig cells and spermatogonia in the testis, in many epithelia of adult mice, and in the two other steroidogenic cell types, adrenal cortex cells and ovarian follicle cells. Embryonic tissues which showed strong activity of the reporter gene included the telencephalon, the genital ridge, and the notochord. This expression pattern closely resembles the endogenous one, indicating that the 5′ FMR1 gene promoter region used in this study contains most cis-acting elements regulating FMR1 transcription
- Published
- 2017
8. Homozygosity of the cystic fibrosis (CF) gene allele IVS8-(5T) in a Tamil male with congenital bilateral absence of the vas deferens (CBAVD)
- Author
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Fokstuen, S., Balakrishnan, J., Kotzot, D., Hergersberg, M., Hobi, Ch, Fokstuen, S., Balakrishnan, J., Kotzot, D., Hergersberg, M., and Hobi, Ch
- Published
- 2017
9. Tissue-specific expression of a FMR1/beta-galactosidase fusion gene in transgenic mice
- Author
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Hergersberg, M, Matsuo, K, Gassmann, M, Schaffner, W, Lüscher, B, Rülicke, T, Aguzzi, A, University of Zurich, and Hergersberg, M
- Subjects
2716 Genetics (clinical) ,1311 Genetics ,10208 Institute of Neuropathology ,1312 Molecular Biology ,570 Life sciences ,biology ,610 Medicine & health - Published
- 1995
- Full Text
- View/download PDF
10. The LTR promoter of the rat oncomodulin gene is regulated by cell-line specific accessibility in the LTR U3 region
- Author
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Rentsch, J. M., Hergersberg, M., Banville, D., Berchtold, Martin Werner, Rentsch, J. M., Hergersberg, M., Banville, D., and Berchtold, Martin Werner
- Abstract
Udgivelsesdato: 1 March 2006, By germline insertion, a long terminal repeat (LTR) of an intracisternal A-particle type IAP retrovirus has overtaken the transcriptional control of the rat oncomodulin (OM) gene, which codes for a high affinity Ca2+-binding protein with modulatory capacity. In order to get insights into regulatory mechanisms of LTR directed OM gene expression we tested promoter activity of this LTR by transient transfection of transformed rat fibroblasts with this sequence placed 5' of the human growth hormone hGH reporter gene. The OM LTR is a strong promoter but does not follow an expression pattern similar to the one of the OM gene. Genomic sequencing showed a good correlation between CpG hypomethylation in the OM LTR and OM transcription among various cell lines and tissues. DNase I mapping of a 18 kb fragment containing the OM gene and 5' flanking sequences revealed cell-line specific hypersensitivity sites located within the U3 region of the LTR element. Several cis-elements in the OM LTR promoter exhibiting cell-line specific occupancy were identified by in vivo DMS-footprinting. Detailed analysis of protein interactions with two such sequence elements in vitro revealed binding of ubiquitously expressed nuclear factors within an AP-1 (activator protein 1) and a intracisternal A-particle upstream enhancer recognition sequence. Protein occupancy to the latter sequence is significantly reduced by CpG methylation. These results indicate that cell-line specificity of OM expression is dictated by factor accessibility to the LTR promoter.
- Published
- 2006
11. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation
- Author
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Kotzot, D., Schmitt, S., Bernasconi, F., Robinson, W.P., Lurie, I.W., Ilyina, H., Méhes, K., Hamel, B.C.J., Otten, B.J., Hergersberg, M., Werder, E., Schoenle, E., and Schinzel, A.
- Subjects
GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) - Abstract
Contains fulltext : 21435___.PDF (Publisher’s version ) (Open Access)
- Published
- 1995
12. TOWARDS THE CLONING OF THE WAS-GENE LOCUS - LINKAGE AND PHYSICAL MAPPING
- Author
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Meindl, A, Schindelhauer, D, Hellebrand, H, Hergersberg, M, Ross, M, Monaco, A, and Meitinger, T
- Published
- 1994
13. High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH
- Author
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Bruder, CEG, Hirvela, C, Tapia-Paez, I, Fransson, I, Segraves, R, Hamilton, G, Zhang, XX, Evans, DG, Wallace, AJ, Baser, ME, Zucman-Rossi, J, Hergersberg, M, Boltshauser, E, Papi, L, Rouleau, GA, Poptodorov, G, Jordanova, A, Rask-Andersen, H, Kluwe, L, Mautner, V, Sainio, M, Hung, G, Mathiesen, T, Moller, C, Pulst, SM, Harder, Henrik, Heiberg, A, Honda, M, Miimura, M, Sahlen, S, Blennow, E, Albertson, DG, Pinkel, D, Dumanski, JP, Bruder, CEG, Hirvela, C, Tapia-Paez, I, Fransson, I, Segraves, R, Hamilton, G, Zhang, XX, Evans, DG, Wallace, AJ, Baser, ME, Zucman-Rossi, J, Hergersberg, M, Boltshauser, E, Papi, L, Rouleau, GA, Poptodorov, G, Jordanova, A, Rask-Andersen, H, Kluwe, L, Mautner, V, Sainio, M, Hung, G, Mathiesen, T, Moller, C, Pulst, SM, Harder, Henrik, Heiberg, A, Honda, M, Miimura, M, Sahlen, S, Blennow, E, Albertson, DG, Pinkel, D, and Dumanski, JP
- Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CON methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.
- Published
- 2001
14. Epidermodysplasia Verruciformis in a HIV-Positive Patient Homozygous for the c917A→T Polymorphism in the TMC8/EVER2 Gene
- Author
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Hohenstein, E., primary, Rady, P.L., additional, Hergersberg, M., additional, Huber, A.R., additional, Tyring, S.K., additional, Bregenzer, T., additional, Streit, M., additional, and Itin, P., additional
- Published
- 2008
- Full Text
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15. 260 Mutation complexe du gène Peripherin/RDS dans une famille avec retinal pattern dystrophy
- Author
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Pajic, B., primary, Weigell-Weber, M., additional, Schipper, I., additional, Kryenbühl, C.H., additional, Buechi, E., additional, Hergersberg, M., additional, and Spiegel, R., additional
- Published
- 2005
- Full Text
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16. Thalassämie-Syndrome: Klinik und Diagnose
- Author
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Huber, A, primary, Ottiger, C, additional, Risch, L, additional, Regenass, S, additional, Hergersberg, M, additional, and Herklotz, R, additional
- Published
- 2004
- Full Text
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17. Anomale Hämoglobine: Erscheinungsbilder und Abklärung
- Author
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Huber, AR, primary, Ottiger, C, additional, Risch, L, additional, Regenass, S, additional, Hergersberg, M, additional, and Herklotz, R, additional
- Published
- 2004
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18. Hämoglobinopathien: Pathophysiologie und Klassifizierung
- Author
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Huber, AR, primary, Ottiger, C, additional, Risch, L, additional, Regenass, S, additional, Hergersberg, M, additional, and Herklotz, R, additional
- Published
- 2004
- Full Text
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19. Schizophrenia and smoking: Evidence for a common neurobiological basis?
- Author
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Stassen, H.H., primary, Bridler, R., additional, H�gele, S., additional, Hergersberg, M., additional, Mehmann, B., additional, Schinzel, A., additional, Weisbrod, M., additional, and Scharfetter, C., additional
- Published
- 2000
- Full Text
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20. Cloned transcription factor MTF-1 activates the mouse metallothionein I promoter.
- Author
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Radtke, F., primary, Heuchel, R., additional, Georgiev, O., additional, Hergersberg, M., additional, Gariglio, M., additional, Dembic, Z., additional, and Schaffner, W., additional
- Published
- 1993
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21. McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings.
- Author
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Jung, Hans H., Hergersberg, Martin, Kneifel, Stefan, Alkadhi, Hatem, Schiess, Regula, Weigell-Weber, Maike, Daniels, Geoff, Kollias, Spyros, Hess, Klaus, Jung, H H, Hergersberg, M, Kneifel, S, Alkadhi, H, Schiess, R, Weigell-Weber, M, Daniels, G, Kollias, S, and Hess, K
- Published
- 2001
- Full Text
- View/download PDF
22. Homozygosity of the cystic fibrosis (CF) gene allele IVS8-(5T) in a Tamil male with congenital bilateral absence of the vas deferens (CBAVD)
- Author
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Fokstuen, S., Balakrishnan, J., Kotzot, D., Hergersberg, M., Hobi, Ch, Fokstuen, S., Balakrishnan, J., Kotzot, D., Hergersberg, M., and Hobi, Ch
23. Molecular cloning and partial characterization of the gene for granule-bound starch synthase from a wildtype and an amylose-free potato (Solanum tuberosum L.)
- Author
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Visser, R.G.F., primary, Hergersberg, M., additional, Van Der Leij, F.R., additional, Jacobsen, E., additional, Witholt, B., additional, and Feenstra, W.J., additional
- Published
- 1989
- Full Text
- View/download PDF
24. Homozygosity of the cystic fibrosis () gene allele IVS8-(5T) in a Tamil male with congenital bilateral absence of the vas deferens (CBAVD).
- Author
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Fokstuen, S., Balakrishnan, J., Kotzot, D., Hergersberg, M., and Hobi, Ch.
- Abstract
Discusses the homozygosity of the cystic fibrosis (CF) gene allele IVS8-(5T) in a Tamil male with congenital bilateral absence of the vas deferens (CBAVD). Isolated CBAVD in populations other than Caucasians; Effect of CF transmembrane conductance regulator gene mutation.
- Published
- 2000
- Full Text
- View/download PDF
25. Corneal dystrophies and degenerations: a molecular genetics approach.
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Hergersberg, M.
- Subjects
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DYSTROPHY , *NONFICTION - Abstract
Reviews the book "Corneal Dystrophies and Degenerations: A Molecular Genetics Approach," edited by Ming X. Wang.
- Published
- 2004
- Full Text
- View/download PDF
26. Deletions in the spinal muscular atrophy gene region in a newborn with neuropathy and extreme generalized muscular weakness
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Eugen Boltshauser, Alice Hagmann, Markus Glatzel, Martin Hergersberg, Adriano Aguzzi, Sibylla Achermann, Joachim E. Fischer, Andrea Capone, Jörg Ersch, University of Zurich, and Hergersberg, M
- Subjects
Male ,10039 Institute of Medical Genetics ,Biopsy ,10208 Institute of Neuropathology ,610 Medicine & health ,Biology ,Muscular Atrophy, Spinal ,Atrophy ,Anterior Horn Cell ,medicine ,Humans ,Peripheral Nerves ,2735 Pediatrics, Perinatology and Child Health ,Respiratory system ,Muscle, Skeletal ,Floppy Infant ,spinal muscular atrophy ,Muscle contracture ,Neurons ,Homozygote ,Infant, Newborn ,Skeletal muscle ,General Medicine ,Spinal muscular atrophy ,Anatomy ,medicine.disease ,floppy infant ,Axons ,Microscopy, Electron ,Facial muscles ,2728 Neurology (clinical) ,medicine.anatomical_structure ,Spinal Cord ,nervous system ,SMN gene ,neonatal neuropathy ,Pediatrics, Perinatology and Child Health ,Chromosomes, Human, Pair 5 ,570 Life sciences ,biology ,Neurology (clinical) ,Chromosome Deletion - Abstract
A newborn presented with respiratory insufficiency requiring artificial ventilation, inability to swallow, lack of spontaneous movements including the facial muscles, and areflexia. Nerve conduction velocities were not recordable. Molecular analysis showed a homozygous deletion in the spinal muscular atrophy (SMN) gene region on chromosome 5q. Pathological and neuropathological examination revealed a normal number of anterior horn cells, hypomyelinated axons in peripheral nerves and some atrophy of skeletal muscle fibres in combination with sarcoplasmic glycogen accumulation. This observation illustrates that severe congenital neuropathy can result from deletions in the SMN gene.
- Published
- 2000
27. Detection of germline rearrangements in patients with α- and β-thalassemia using high resolution array CGH.
- Author
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Blattner A, Brunner-Agten S, Ludin K, Hergersberg M, Herklotz R, Huber AR, and Röthlisberger B
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- Adolescent, Adult, Aged, Base Sequence, Child, Child, Preschool, Chromosome Breakpoints, Comparative Genomic Hybridization, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Molecular Sequence Data, Multigene Family, Promoter Regions, Genetic, Young Adult, alpha-Thalassemia diagnosis, beta-Thalassemia diagnosis, Gene Rearrangement, Germ-Line Mutation, alpha-Globins genetics, alpha-Thalassemia genetics, beta-Globins genetics, beta-Thalassemia genetics
- Abstract
Approximately 80% of α-thalassemia mutations are deletions in the α-globin cluster on chromosome 16 and about 10% of β-thalassemia mutations are deletions in the β-globin gene cluster on chromosome 11. Larger deletions involving the β-globin gene cluster lead to (δβ)-, (γδβ)-, (εγδβ)-thalassemia, or hereditary persistence of fetal hemoglobin (HPFH). Array comparative genomic hybridization (CGH) was applied to screen for deletions in the α- and β-globin gene clusters not detected by routine gap-PCR. In total, in 13 patients with hypochromia and inclusion bodies (IBs) the α-globin gene cluster was analyzed and in 13 patients with increased fetal hemoglobin levels with or without hypochromia the β-globin gene cluster was examined. All samples were subsequently investigated by multiplex ligation-dependent probe amplification (MLPA). In 9 out of 13 patients deletions of the α-globin gene cluster were identified; 5 of these deletions remove the entire α-globin cluster and extend to the telomere. Additional sequencing of the remaining 4 patients revealed polyadenylation mutation in 1 of them. 7 deletions were identified in the β-globin gene cluster in 13 patients. Additional sequencing of the remaining 6 patients revealed mutations in one of the γ-globin gene promoters in 3 of them and a KLF1-mutation in 1 of them. Array CGH is a reliable method to screen for deletions in thalassemia and hemoglobinopathy. The method offers the advantage of a high resolution with the possibility to characterize breakpoints on sequence level., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
28. A new stable alpha chain variant: Hb Basel [alpha14(A12)Trp-->Leu (alpha1)].
- Author
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Hergersberg M, Brunner-Agten S, Kühne T, Paulussen M, and Huber AR
- Subjects
- Adolescent, Family Health, Female, Humans, Male, Middle Aged, Portugal ethnology, Switzerland, beta-Thalassemia diagnosis, Genetic Variation genetics, Mutation, Missense genetics, alpha-Globins genetics, beta-Thalassemia genetics
- Abstract
We describe a heterozygosity for a new missense mutation on the alpha1-globin gene of an 18-year-old woman of Portuguese ancestry with severe hypochromic anemia and iron deficiency. Hemoglobin (Hb) analysis by high performance liquid chromatography (HPLC) found a prominent peak constituting about 12% of total Hb. Sequencing of the globin genes of the index patient found the mutation alpha14(A12)Trp-->Leu (alpha1), HBA1:c.44G
- Published
- 2010
- Full Text
- View/download PDF
29. Compound heterozygosity of Hb Hamilton and de novo mutated HbM Saskatoon.
- Author
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Brunner-Agten S, Hergersberg M, Herklotz R, Hirt A, and Huber AR
- Subjects
- Adult, Child, Child, Preschool, Chronic Disease, Cyanosis diagnosis, Cyanosis genetics, Female, Humans, Male, Middle Aged, Genetic Carrier Screening, Hemoglobins, Abnormal genetics, Mutation genetics
- Published
- 2010
- Full Text
- View/download PDF
30. Epidermodysplasia verruciformis in a HIV-positive patient homozygous for the c917A-->T polymorphism in the TMC8/EVER2 gene.
- Author
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Hohenstein E, Rady PL, Hergersberg M, Huber AR, Tyring SK, Bregenzer T, Streit M, and Itin P
- Subjects
- AIDS-Related Opportunistic Infections complications, AIDS-Related Opportunistic Infections pathology, Adult, Alanine, Epidermodysplasia Verruciformis pathology, Epidermodysplasia Verruciformis virology, Female, HIV Infections congenital, HIV Infections pathology, Homozygote, Humans, Mutation, Papillomaviridae isolation & purification, Threonine, AIDS-Related Opportunistic Infections genetics, Epidermodysplasia Verruciformis genetics, HIV Infections genetics, Immunocompromised Host, Membrane Proteins genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive disorder characterized by widespread and persistent infection with human papilloma virus (HPV) and a risk of malignant degeneration. Most cases of EV are caused by mutations in the two EV genes, EVER1/TMC6 and EVER2/TMC8. The clinical presentation of EV takes two different forms, which coexist in most cases. Over a period of years, patients develop plane warts and pityriasis versicolor-like lesions. Sixteen cases of EV in HIV-positive patients have been clinically investigated and reported in the literature. However, different inherited susceptibilities towards HPV infection in immunodeficient patients, like HIV-positive patients, have only rarely been addressed., Observation: We describe a 22-year-old female patient with a congenital HIV infection, who presented with slowly progressing and confluent erythematous papules on her hands and hypopigmented macules on her extremities. The histopathology was typical for EV, and HPV5 was detected by PCR and reverse hybridization. The 44-year-old HIV-positive mother has no typical EV lesions. The patient is homozygous for an A to T single nucleotide polymorphism (SNP) at position 917 of the TMC8/EVER2 gene. The mother of the patient is heterozygous for this SNP., Conclusion: These results support the hypothesis that the combination of immunodeficiency and a susceptibility allele may contribute to the differences in occurrence of EV in HIV-positive patients., (Copyright (c) 2008 S. Karger AG, Basel.)
- Published
- 2009
- Full Text
- View/download PDF
31. Homozygosity of Hb G-Coushatta combined with heterozygous IVS-I-110(G>A) in an adult patient.
- Author
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Hergersberg M, Herklotz R, Zerlauth M, and Huber AR
- Subjects
- Adult, Heterozygote, Homozygote, Humans, Male, Turkey, Hemoglobins, Abnormal genetics, beta-Thalassemia genetics
- Published
- 2008
32. Phenotypic variability of a distinct deletion in McLeod syndrome.
- Author
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Miranda M, Castiglioni C, Frey BM, Hergersberg M, Danek A, and Jung HH
- Subjects
- Chorea complications, Chorea pathology, DNA Mutational Analysis, Genetic Diseases, X-Linked complications, Genetic Diseases, X-Linked pathology, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Tomography, X-Ray Computed methods, Amino Acid Transport Systems, Neutral genetics, Chorea genetics, Genetic Diseases, X-Linked genetics, Phenotype, Sequence Deletion, Siblings
- Abstract
The X-linked McLeod neuroacanthocytosis syndrome strongly resembles Huntington's disease and has been reported in various countries world-wide. Herein, we report two Chilean brothers with predominant psychiatric features at disease onset including schizophrenia-like psychosis and obsessive compulsive disorder. Molecular genetic analysis revealed a small deletion in the XK gene (938-942delCTCTA), which has been already described in a North American patient of Anglo-Saxon descent and a Japanese family, presenting with seizures, muscle atrophy or chorea yet absence of psychiatric features. These findings argue against a founder effect and indicate a profound phenotypic variability associated with the 938-942delCTCTA deletion. Our report supports the inclusion of McLeod syndrome in the differential diagnosis of Huntington's disease as well as acute psychosis in male subjects., (2007 Movement Disorder Society)
- Published
- 2007
- Full Text
- View/download PDF
33. A novel complex mutation event in the peripherin/RDS gene in a family with retinal pattern dystrophy.
- Author
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Pajic B, Weigell-Weber M, Schipper I, Kryenbühl C, Büchi ER, Spiegel R, and Hergersberg M
- Subjects
- Adult, Aged, DNA Mutational Analysis, Exons genetics, Female, Fluorescein Angiography, Genes, Dominant, Humans, Male, Middle Aged, Pedigree, Peripherins, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Intermediate Filament Proteins genetics, Membrane Glycoproteins genetics, Mutation, Nerve Tissue Proteins genetics, Retinal Degeneration genetics
- Abstract
Purpose: To report a complex mutation in the peripherin/RDS gene found in a family in whom retinal pattern dystrophy is segregating as an autosomal dominant trait., Methods: Clinical data were collected from family members of a large Swiss family affected by autosomal dominant retinal pattern dystrophy. Single strand conformation polymorphism (SSCP) analysis of the candidate gene peripherin/RDS and subsequent sequencing of the first exon were performed., Results: Pattern dystrophy of the retina was suspected in 18 family members aged 30 years or older. Assuming a homogeneous phenotype, the candidate locus peripherin/RDS was investigated. SSCP analysis of the first exon of the peripherin/RDS gene showed an aberrant pattern in 18 affected individuals. Direct sequencing of polymerase chain reaction products detected a complex mutation, del265-268GCCA ins AGGGCC, leading to a stop codon at amino acid position 99., Conclusion: To our knowledge, we report the first complex mutation in the peripherin/RDS gene as the cause of a mild macular phenotype, supporting the importance of molecular diagnosis in genetic counseling.
- Published
- 2006
- Full Text
- View/download PDF
34. The LTR promoter of the rat oncomodulin gene is regulated by cell-line specific accessibility in the LTR U3 region.
- Author
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Rentsch JM, Hergersberg M, Banville D, and Berchtold MW
- Subjects
- Animals, Cells, Cultured, Rats, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Fibroblasts metabolism, Gene Expression Regulation genetics, Promoter Regions, Genetic genetics, Terminal Repeat Sequences genetics
- Abstract
By germline insertion, a long terminal repeat (LTR) of an intracisternal A-particle type IAP retrovirus has overtaken the transcriptional control of the rat oncomodulin (OM) gene, which codes for a high affinity Ca2+-binding protein with modulatory capacity. In order to get insights into regulatory mechanisms of LTR directed OM gene expression we tested promoter activity of this LTR by transient transfection of transformed rat fibroblasts with this sequence placed 5' of the human growth hormone hGH reporter gene. The OM LTR is a strong promoter but does not follow an expression pattern similar to the one of the OM gene. Genomic sequencing showed a good correlation between CpG hypomethylation in the OM LTR and OM transcription among various cell lines and tissues. DNase I mapping of a 18 kb fragment containing the OM gene and 5' flanking sequences revealed cell-line specific hypersensitivity sites located within the U3 region of the LTR element. Several cis-elements in the OM LTR promoter exhibiting cell-line specific occupancy were identified by in vivo DMS-footprinting. Detailed analysis of protein interactions with two such sequence elements in vitro revealed binding of ubiquitously expressed nuclear factors within an AP-1 (activator protein 1) and a intracisternal A-particle upstream enhancer recognition sequence. Protein occupancy to the latter sequence is significantly reduced by CpG methylation. These results indicate that cell-line specificity of OM expression is dictated by factor accessibility to the LTR promoter.
- Published
- 2006
- Full Text
- View/download PDF
35. PK Aarau: first homozygous nonsense mutation causing pyruvate kinase deficiency.
- Author
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Sedano IB, Röthlisberger B, Délèze G, Ottiger C, Panchard MA, Spahr A, Hergersberg M, Bürgi W, and Huber A
- Subjects
- Anemia, Hemolytic, Congenital Nonspherocytic enzymology, Cyclic AMP-Dependent Protein Kinases genetics, Female, Humans, Infant, Newborn, Male, Pedigree, Anemia, Hemolytic, Congenital Nonspherocytic genetics, Codon, Nonsense, Cyclic AMP-Dependent Protein Kinases deficiency
- Published
- 2004
- Full Text
- View/download PDF
36. Quantitative monitoring of BCR--ABL transcript--suggestion of a simplified approach considering inaccuracy of measurement and calibration.
- Author
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Röthlisberger B, Herklotz R, Hergersberg M, Stricker C, Bargetzi M, and Huber AR
- Subjects
- Calibration, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Reference Standards, Reverse Transcriptase Polymerase Chain Reaction standards, Sensitivity and Specificity, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, RNA, Neoplasm analysis, Research Design, Reverse Transcriptase Polymerase Chain Reaction methods
- Abstract
According to standard-protocols, real time quantitative RT-PCR (RQ-PCR) for quantification of BCR-ABL fusion transcripts in CML patients is performed with the construction of a standard curve for each run, each sample is analyzed at least in duplicate and 10-40 ml peripheral blood are processed. This approach is appropriate for a research laboratory, but is not suitable for a routine laboratory setting. We show that the calibration curve based on the common 5 dilution standards (between 10 and 10(6) copies) is strongly influenced by the large variability of the measurements below 100 copies of the gene. In other words, including a standard with 10 copies is a source of error, which cannot be reduced through the construction of a standard curve with each run. Adding additional dilutions between 10 and 100 copies to the standard curve, the variance of the obtained curve is much reduced. As a conclusion, it is unnecessary to construct a calibration curve with each run since only negligible inaccuracy of calibration is added to the inaccuracy of measurement. Running of the samples in duplicate seems unnecessary since the inaccuracy of the method can be correctly estimated. Finally, we propose a standardized collection and isolation of total RNA from only 2.5 ml blood using an integrated system, which allows RNA stabilization for up to 5 days and provides snapshots of BCR-ABL fusion transcripts with higher accuracy than with non-stabilized blood samples.
- Published
- 2004
- Full Text
- View/download PDF
37. [Genetic analysis and immunophenotyping in the diagnosis of hematological disease].
- Author
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Hergersberg M, Röthlisberger B, Heijnen IA, and Huber AR
- Subjects
- Chromosome Mapping, Cytogenetic Analysis, DNA Mutational Analysis, Flow Cytometry, Genetic Counseling, Hematologic Diseases diagnosis, Hematologic Diseases immunology, Hematologic Neoplasms diagnosis, Hematologic Neoplasms immunology, Humans, Hematologic Diseases genetics, Hematologic Neoplasms genetics, Immunophenotyping, Molecular Diagnostic Techniques
- Abstract
The developments in the fields of genetics and immunology and the application of these informations have significant consequences for the diagnosis of hematological diseases. The present article gives an introduction into the principles of several modern diagnostic techniques, which are applied in the diagnosis of hematological diseases. In addition, it summarizes the application of these techniques in the diagnosis of several acquired and inherited diseases. The most important method of immunophenotyping is FACS (fluorescence activated cell sorting) analysis, which is based on the automated recognition of fluorescently labelled monoclonal antibodies bound to specific antigens on the surface or in the cytoplasm of different cell populations of the immune system. Techniques from molecular biology and from cytogenetics are also relevant for the diagnosis of hematological diseases: they allow the identification of changes of the genetic material on the level of DNA (molecular biology) and chromosomes (cytogenetics). Molecular biological and cytogenetic methods coalesce in the field of molecular cytogenetics, which renders possible the identification of chromosome mutations, which are invisible by the classical cytogenetical approach, and difficult to detect by routine molecular biological analysis. Most hematological malignancies are associated with genomic changes, which can be identified by cytogenetic and/or molecular biological methods. These genetic changes usually correspond with a specific pattern of surface antigens of the tumour cells, which can be identified by FACS. The different mutations in different genes causing a large number of inherited hematological diseases can often be found by molecular analysis, too. For hematological neoplasias, the exact definition of the causative mutations is increasingly important for therapeutic decisions and follow-up analysis of minimal residual disease. For inherited diseases, the identification of mutations is often the basis for a correct genetic counselling of the family.
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- 2004
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38. Clinical description and exclusion of candidate genes in a novel autosomal recessively inherited vitreoretinal dystrophy.
- Author
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Sarra GM, Weigell-Weber M, Kotzot D, Niemeyer G, Messmer E, and Hergersberg M
- Subjects
- Aged, Atrophy, Cataract diagnosis, Electroretinography, Eye Diseases, Hereditary diagnosis, Female, Genetic Linkage, Genetic Markers, Humans, Male, Myopia diagnosis, Pigment Epithelium of Eye pathology, Polymerase Chain Reaction, Retinal Degeneration diagnosis, Vision Disorders genetics, Visual Field Tests, Visual Fields, Cataract genetics, Eye Diseases, Hereditary genetics, Genes, Recessive, Myopia genetics, Retinal Degeneration genetics, Vitreous Body pathology
- Abstract
Objectives: To describe the clinical phenotype of a novel autosomal recessively inherited vitreoretinal dystrophy in one generation of a family originating from eastern Switzerland., Methods: A clinical study including electroretinographic investigations followed by laboratory-based genetic and molecular analysis. Four affected and 3 unaffected members of the family were examined. Ten candidate regions were tested by linkage analysis with highly polymorphic molecular markers or with intragenic restriction fragment length polymorphisms., Results: Of 8 siblings,4 were affected, showing high myopia with pronounced vitreous liquefaction, retinitis pigmentosa-like retinal degeneration, diffuse retinal pigment epithelium atrophy, macular staphylomata, and premature cataract formation. Strikingly abnormal results on electroretinograms, affecting both the rod and the cone systems, revealed an extensive defect of retinal function, unlike those usually found in pathologic myopia. No extraocular manifestations were observed. Three types of nonsyndromic high myopia, Stickler syndrome I, II, and III, Wagner syndrome, Knobloch syndrome, Goldmann-Favre dystrophy, and multiple vitreoretinopathies were excluded by linkage analysis., Conclusions: The reported phenotype as well as the results of molecular linkage analysis in the siblings described here suggest an autosomal recessively inherited vitreoretinal dystrophy, which, to our knowledge, has not been described until now.
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- 2003
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- View/download PDF
39. Genomewide homozygosity mapping and molecular analysis of a candidate gene located on 22q13 (fibulin-1) in a previously undescribed vitreoretinal dystrophy.
- Author
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Weigell-Weber M, Sarra GM, Kotzot D, Sandkuijl L, Messmer E, and Hergersberg M
- Subjects
- Aged, Base Sequence, DNA Mutational Analysis, Extracellular Matrix Proteins genetics, Eye Diseases, Hereditary pathology, Female, Genes, Recessive, Haplotypes, Homozygote, Humans, Lod Score, Male, Microsatellite Repeats, Molecular Biology, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, Retinal Degeneration pathology, Reverse Transcriptase Polymerase Chain Reaction, Calcium-Binding Proteins genetics, Chromosome Mapping, Chromosomes, Human, Pair 22 genetics, Eye Diseases, Hereditary genetics, Retinal Degeneration genetics, Vitreous Body pathology
- Abstract
Objectives: To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [FBLN1])., Methods: Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [cM]) and mutation analysis of the complete coding region of FBLN1., Results: Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 cM from D22S444 (centromeric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta = 0). A mutation analysis of the complete coding region of FBLN1, which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms., Conclusions: A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1.
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- 2003
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40. McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement.
- Author
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Jung HH, Hergersberg M, Vogt M, Pahnke J, Treyer V, Röthlisberger B, Kollias SS, Russo D, and Frey BM
- Subjects
- Blotting, Western, Brain Diseases diagnosis, Brain Diseases genetics, Chromosomes, Human, X, Genetic Linkage, Hematologic Diseases diagnosis, Hematologic Diseases genetics, Humans, Immunohistochemistry, Magnetic Resonance Imaging, Male, Middle Aged, Muscle, Skeletal pathology, Neuromuscular Diseases diagnosis, Neuromuscular Diseases genetics, Pedigree, Polymorphism, Genetic, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Syndrome, Tomography, Emission-Computed, Amino Acid Transport Systems, Neutral genetics, Chorea genetics, Kell Blood-Group System genetics, Mutation, Missense, Phenotype
- Abstract
Background: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement., Study Design and Methods: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET)., Results: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET., Conclusion: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.
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- 2003
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41. Spondylo-ocular syndrome: a new entity with crystalline lens malformation, cataract, retinal detachment, osteoporosis, and platyspondyly.
- Author
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Rudolph G, Kalpadakis P, Bettecken T, Lichtner P, Haritoglou C, Hergersberg M, Meitinger T, and Schmidt H
- Subjects
- Abnormalities, Multiple diagnosis, Adult, Cataract diagnosis, Child, Collagen genetics, Consanguinity, DNA Mutational Analysis, Eye Proteins, Female, Homeodomain Proteins genetics, Humans, Lens, Crystalline pathology, Male, Microsatellite Repeats genetics, Middle Aged, Osteoporosis diagnosis, PAX6 Transcription Factor, Paired Box Transcription Factors, Pedigree, Polymerase Chain Reaction, Repressor Proteins, Retinal Detachment diagnosis, Spine pathology, Syndrome, Abnormalities, Multiple genetics, Cataract genetics, Lens, Crystalline abnormalities, Osteoporosis genetics, Retinal Detachment genetics, Spine abnormalities
- Abstract
Purpose: To define a new clinical entity in a consanguineous family with six children affected by a spondylo-ocular syndrome, including cataract, crystalline lens malformation, retinal detachment, osteoporosis, and platyspondyly. To analyze candidate genes of connective tissue disorders as a possible underlying disorder and to demonstrate especially the ocular phenotype., Design: Observational case series., Methods: Consanguineous parents, one unaffected sibling and five affected children with clinical features of spondylo-ocular syndrome, were demonstrated. Clinical examination, radiologic, laboratory, and cytogenetic as well as moleculargenetic analyses were performed. The segregation of flanking marker alleles of three collagen genes and the interval for osteoporosis-pseudoglioma syndrome were analyzed. Two microsatellite markers located within Pax6CA/GT region were tested for homozygosity., Results: On laboratory investigation a normal excretion of amino acids, mucopolysaccharides, and oligosaccharides could be found. The karyotype was normal. Complete radiologic examination in one index patient revealed a generalized moderate osteoporosis, platyspondyly with fish bone appearance, and greatly enlarged intervertebral spaces. The candidate genes known to be in Stickler syndrome as well as linkage to the osteoporosis-pseudoglioma syndrome candidate region could be excluded. None of the affected showed homozygosity for the Pax6 microsatellite markers., Conclusions: We conclude that the phenotype and the clinical features in this family defines a new Mendelian disorder. It remains to be seen what kind of molecule shared by eye and bone is involved.
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- 2003
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- View/download PDF
42. X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15.
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Bader I, Brandau O, Achatz H, Apfelstedt-Sylla E, Hergersberg M, Lorenz B, Wissinger B, Wittwer B, Rudolph G, Meindl A, and Meitinger T
- Subjects
- DNA Mutational Analysis, Exons genetics, GTP-Binding Proteins, Genetic Linkage, Genetic Testing, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Open Reading Frames genetics, Pedigree, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Proteins genetics, Sequence Analysis, DNA, Carrier Proteins genetics, Chromosomes, Human, X genetics, Eye Proteins, Genetic Diseases, X-Linked genetics, Mutation, Retinitis Pigmentosa genetics
- Abstract
Purpose: A comprehensive screening was conducted for RP2 and retinitis pigmentosa GTPase regulator (RPGR) gene mutations including RPGR exon ORF15 in 58 index patients. The frequency of RPGR mutations was assessed in families with definite X-linked recessive disease (xlRP), and a strategy for analyzing the highly repetitive mutational hot spot in exon ORF15 is provided., Methods: Fifty-eight apparently unrelated index-patients were screened for mutations in all coding exons of the RP2 and the RPGR genes, including splice-sites, by single-strand conformation polymorphism (SSCP) analysis, except for RPGR exon ORF15. A strategy for directly sequencing the large repetitive stretch of exon ORF15 from a 1.6-kb PCR-product was developed. According to pedigree size and evidence for X linkage, families were subdivided into three categories., Results: Screening of 58 xlRP families revealed RP2 mutations in 8% and RPGR mutations in 71% of families with definite X-linked inheritance. Mutations clustered within a approximately 500-bp stretch in exon ORF15. In-frame sequence alterations in exon ORF15 ranged from the deletion of 36 bp to the insertion of 75 bp., Conclusions: Mutations in the RPGR gene are estimated to cause 15% to 20% of all cases of RP, higher than any other single RP locus. This report provides a detailed strategy to analyze the mutational hot spot in RPGR exon ORF15, which cannot be screened by standard procedures. The discrepancy of the proportion of families linked to the RP3 locus and those having RPGR mutations is resolved in a subset of families with definite X linkage.
- Published
- 2003
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43. A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications.
- Author
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Buckley PG, Mantripragada KK, Benetkiewicz M, Tapia-Páez I, Diaz De Ståhl T, Rosenquist M, Ali H, Jarbo C, De Bustos C, Hirvelä C, Sinder Wilén B, Fransson I, Thyr C, Johnsson BI, Bruder CE, Menzel U, Hergersberg M, Mandahl N, Blennow E, Wedell A, Beare DM, Collins JE, Dunham I, Albertson D, Pinkel D, Bastian BC, Faruqi AF, Lasken RS, Ichimura K, Collins VP, and Dumanski JP
- Subjects
- Chromosome Mapping methods, Female, Gene Amplification genetics, Gene Deletion, Gene Dosage, Genes, Tumor Suppressor, Humans, Male, Nucleic Acid Hybridization methods, Chromosomes, Human, Pair 22 genetics, Genomics methods, Molecular Diagnostic Techniques methods, Oligonucleotide Array Sequence Analysis methods
- Abstract
We have constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number variation. This chromosome 22 array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb. To demonstrate the utility of the array, we have applied it to profile acral melanoma, dermatofibrosarcoma, DiGeorge syndrome and neurofibromatosis 2. We accurately diagnosed homozygous/heterozygous deletions, amplifications/gains, IGLV/IGLC locus instability, and breakpoints of an imbalanced translocation. We further identified the 14-3-3 eta isoform as a candidate tumor suppressor in glioblastoma. Two significant methodological advances in array construction were also developed and validated. These include a strictly sequence defined, repeat-free, and non-redundant strategy for array preparation. This approach allows an increase in array resolution and analysis of any locus; disregarding common repeats, genomic clone availability and sequence redundancy. In addition, we report that the application of phi29 DNA polymerase is advantageous in microarray preparation. A broad spectrum of issues in medical research and diagnostics can be approached using the array. This well annotated and gene-rich autosome contains numerous uncharacterized disease genes. It is therefore crucial to associate these genes to specific 22q-related conditions and this array will be instrumental towards this goal. Furthermore, comprehensive epigenetic profiling of 22q-located genes and high-resolution analysis of replication timing across the entire chromosome can be studied using our array.
- Published
- 2002
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44. Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina.
- Author
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Wutz K, Sauer C, Zrenner E, Lorenz B, Alitalo T, Broghammer M, Hergersberg M, de la Chapelle A, Weber BH, Wissinger B, Meindl A, and Pusch CM
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Calcium Channels, L-Type genetics, Calcium Signaling, Chromosome Mapping, DNA Primers, Female, Humans, Male, Molecular Sequence Data, Night Blindness genetics, Pedigree, Polymorphism, Single-Stranded Conformational, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid, X Chromosome, Calcium Channels genetics, Eye Diseases genetics, Gene Expression Profiling methods, Mice genetics, Mutation, Retina physiology
- Abstract
X-linked CSNB patients may exhibit myopia, nystagmus, strabismus and ERG abnormalities of the Schubert-Bornschein type. We recently identified the retina-specific L-type calcium channel alpha1 subunit gene CACNA1F localised to the Xp11.23 region, which is mutated in families showing the incomplete type (CSNB2). Here, we report comprehensive mutation analyses in the 48 CACNA1F exons in 36 families, most of them from Germany. All families were initially diagnosed as having the incomplete type of CSNB, except for two which have been designated as Aland Island eye disease (AIED)-like. Out of 33 families, a total of 30 different mutations were identified, of which 24 appear to be unique for the German population. The mutations, 20 of which are published here for the first time, were found to be equally distributed over the entire gene sequence. No mutation could be found in a classic AIED family previously shown to map to the CSNB2 interval. Cacna1f expression in photoreceptor-negative mice strains indicate that the gene is expressed in the outer nuclear, the inner nuclear, and the ganglion cell layer. Such a distribution points to the central role of calcium regulation in the interaction of retinal cells that mediate signal transmission.
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- 2002
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45. Ancestral founder of mutation W283X in the porphobilinogen deaminase gene among acute intermittent porphyria patients.
- Author
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Schneider-Yin X, Hergersberg M, Goldgar DE, Rüfenacht UB, Schuurmans MM, Puy H, Deybach JC, and Minder EI
- Subjects
- Amino Acid Substitution, Female, Genes, Dominant, Haplotypes, Humans, Male, Microsatellite Repeats, Mutation, Pedigree, Polymorphism, Single Nucleotide, Porphyria, Acute Intermittent enzymology, Sequence Analysis, DNA, Hydroxymethylbilane Synthase genetics, Porphyria, Acute Intermittent genetics
- Abstract
Acute intermittent porphyria (AIP) is a low-penetrant autosomal dominant disorder caused by mutations in the porphobilinogen deaminase gene (PBGD). Nearly 60% of all Swiss AIP patients carry a nonsense mutation W283X (G(7916)-->A). In France, the prevalence of W283X is <5%. To determine whether W283X was a founder mutation or originated from multiple de novo events, we studied 25 apparently unrelated W283X families and index patients, 21 of Swiss and 4 of French origins. In the absence of sufficient genealogical data to verify the ancestral background of these W283X families/patients, we identified haplotypes of seven intragenic single nucleotide polymorphisms (SNPs) in the PBGD gene as well as eight microsatellites flanking the PBGD gene covering 9.88 cM in chromosome 11. Molecular cloning and sequencing experiments were required in order to completely resolve the intragenic haplotypes in this study cohort which mainly consisted of single index patients and families with limited members. Thirteen of the 25 W283X families/patients carry a SNP haplotype [C-A-A-A-G-C-W283X-G] and 12 (including four French families) carry a [T-G-G-G-G-C-W283X-G] haplotype. A less conserved microsatellite haplotype was identified among the 25 W283X alleles which allowed us to estimate the age of the mutation. Since W283X is not explained by a methylcytosine mutation, we favor the hypothesis of a single mutational event which took place on the [T-G-G-G-G-C-G] background at approximately 40 generations or 1000 years ago. Around 550 years ago, a recombination event occurred between intron 3 and 10 of the PBGD gene which resulted in the [C-A-A-A-G-C-W283X-G] haplotype only found in a restricted region., (Copyright 2003 S. Karger AG, Basel)
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- 2002
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46. Haplotype analysis in determination of the heredity of erythropoietic protoporphyria among Swiss families.
- Author
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Schneider-Yin X, Rüfenacht UB, Hergersberg M, Schnyder C, Deybach JC, and Minder EI
- Subjects
- Family Health, Female, Ferrochelatase genetics, Founder Effect, Haplotypes, Humans, Male, Microsatellite Repeats, Pedigree, Penetrance, Switzerland, Polymorphism, Single Nucleotide, Porphyria, Hepatoerythropoietic genetics
- Abstract
Defects in the human ferrochelatase gene lead to the hereditary disorder of erythropoietic protoporphyria. The clinical expression of this autosomal dominant disorder requires an allelic combination of a disabled mutant allele and a low-expressed nonmutant allele. Unlike most other erythropoietic protoporphyria populations, mutations identified among Swiss erythropoietic protoporphyria families to date have been relatively homogeneous. In this study, genotype analysis was conducted in seven Swiss erythropoietic protoporphyria families, three carrying mutation Q59X, two carrying mutation insT213, and two carrying mutation delTACAG(580-584). Three different haplotypes of five known intragenic single nucleotide polymorphisms, namely -251 A/G, IVS1-23C/T, 798 G/C, 921 A/G, and 1520C/T, were identified. Each haplotype was shared by families carrying an identical mutation in the ferrochelatase gene indicating a single mutation event for each of the three mutations. These mutations have been present in the Swiss erythropoietic protoporphyria population for a relatively long time as no common haplotypes of microsatellite markers flanking the ferrochelatase gene were found, except of two conserved regions, telomeric of the insT213 allele and centromeric of the delTACAG(580-584)allele, each with a size > 3 cM. Among the nonmutant ferrochelatase alleles, patients from six erythropoietic protoporphyria families shared a common haplotype [-251G; IVS1-23T] of the first two single nucleotide polymorphisms. An exception was the haplotype [-251 A; IVS1-23C] identified in the index patient of one erythropoietic protoporphyria family. These results supported the recent findings that the low expressed allele is tightly linked to a haplotype [-251G; IVS1-23T] of two intragenic single nucleotide polymorphisms in the ferrochelatase gene.
- Published
- 2001
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47. The long form of CDK2 arises via alternative splicing and forms an active protein kinase with cyclins A and E.
- Author
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Ellenrieder C, Bartosch B, Lee GY, Murphy M, Sweeney C, Hergersberg M, Carrington M, Jaussi R, and Hunt T
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Cell Cycle, Cell Line, Chlorocebus aethiops, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinases metabolism, Cyclins, Enzyme Activation, Enzyme Inhibitors, Humans, Isoenzymes, Mice, Molecular Sequence Data, Protein Serine-Threonine Kinases metabolism, Rabbits, Tissue Distribution, Alternative Splicing, CDC2-CDC28 Kinases, Cyclin A metabolism, Cyclin E metabolism, Cyclin-Dependent Kinases genetics, Protein Serine-Threonine Kinases genetics
- Abstract
We have reinvestigated the long form of cyclin-dependent kinase (CDK)2 that is expressed in many rodent cells. We show that the mRNA encoding CDK2L arises by alternative splicing and that the encoded protein can bind to, and be activated by, cyclins A and E. The complex of CDK2L with cyclin A has about half the specific activity of the equivalent CDK2-cyclin A complex. Also, CDK2L--cyclin A is inhibited to the same extent and by the same concentrations of p21(CIP1) as CDK2--cyclin A. The nucleotide sequences of intron V in the human and murine CDK2 genes, where the sequences encoding the 48-residue insert in CDK2L are located, show very high conservation in the position of the alternatively spliced exon and its surroundings. Despite this, we were not able to detect significant expression of CDK2L in human cell lines, although a low level is expressed in COS-1 cells from monkeys.
- Published
- 2001
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48. A novel MSP/DHPLC method for the investigation of the methylation status of imprinted genes enables the molecular detection of low cell mosaicisms.
- Author
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Baumer A, Wiedemann U, Hergersberg M, and Schinzel A
- Subjects
- Adult, Alleles, Angelman Syndrome genetics, Beckwith-Wiedemann Syndrome genetics, Blotting, Southern, Caenorhabditis elegans Proteins, Child, Chromatography, High Pressure Liquid methods, Female, Humans, Infant, Male, Membrane Proteins, Molecular Sequence Data, Nucleic Acid Denaturation, Prader-Willi Syndrome genetics, Reproducibility of Results, Sensitivity and Specificity, Substrate Specificity, Temperature, Time Factors, snRNP Core Proteins, Autoantigens genetics, DNA Methylation, Genomic Imprinting genetics, Mosaicism genetics, Polymerase Chain Reaction methods, Protein Serine-Threonine Kinases genetics, Ribonucleoproteins, Small Nuclear
- Abstract
We describe a new procedure for the analysis of the methlyation status of imprinted genes based on methylation-specific PCR followed by denaturing high performance liquid chromatography (MSP/DHPLC). The method offers a rapid and very reliable alternative to conventional methods used for such purposes such as Southern blots and methylation specific PCR (allele-specific MSP). The efficient resolution of the differentially methylated alleles is demonstrated for two human imprinted genes, namely the SNRPN gene and the LIT1 gene (KCNQ1OT1). Abnormal imprinting of the two genes is associated with the Angelman/Prader-Willi syndromes and the Beckwith-Wiedemann syndrome, respectively. The MSP/DHPLC method is based on PCR amplification of gene segments which show parent-of-origin specific methylation. Genomic DNA is subjected to an in vitro bisulfite treatment prior to PCR amplifications using primers specific for modified DNA. Both alleles are theoretically amplified with equal efficiency and are represented by identically sized PCR products; they differ, however, at a number of positions within the amplified DNA segment. The DHPLC analysis allows a very efficient resolution of the two populations of PCR products. The high sensitivity and quantitative properties of the MSP/DHPLC method are illustrated based on its ability to reveal a low cell mosaicism in an infant with a maternal uniparental disomy 15 (i.e., Prader-Willi syndrome patient). The minor cell line (approximately 8% in blood) was not detectable with conventional molecular analysis. While the detection of low cell mosaicisms of structurally abnormal chromosomes usually relies on cytogenetic studies, the MSP/DHPLC method described here not only offers an alternative at the molecular level, but may also reveal mosaicisms concerning structurally intact chromosomes., (Copyright 2001 Wiley-Liss, Inc.)
- Published
- 2001
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49. High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH.
- Author
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Bruder CE, Hirvelä C, Tapia-Paez I, Fransson I, Segraves R, Hamilton G, Zhang XX, Evans DG, Wallace AJ, Baser ME, Zucman-Rossi J, Hergersberg M, Boltshauser E, Papi L, Rouleau GA, Poptodorov G, Jordanova A, Rask-Andersen H, Kluwe L, Mautner V, Sainio M, Hung G, Mathiesen T, Möller C, Pulst SM, Harder H, Heiberg A, Honda M, Niimura M, Sahlén S, Blennow E, Albertson DG, Pinkel D, and Dumanski JP
- Subjects
- Adolescent, Child, Chromosomes, Human, Pair 22 genetics, Cloning, Molecular, Contig Mapping, DNA chemistry, Female, Gene Deletion, Humans, In Situ Hybridization, Fluorescence, Male, Membrane Proteins genetics, Middle Aged, Neurofibromatosis 2 pathology, Neurofibromin 2, Nucleic Acid Hybridization methods, Sequence Analysis, DNA, Chromosome Deletion, DNA genetics, Neurofibromatosis 2 genetics
- Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CGH methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.
- Published
- 2001
- Full Text
- View/download PDF
50. [Hereditary hearing loss due to mutations in the connexin-26 gene].
- Author
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Weigell-Weber M, Schinzel A, and Hergersberg M
- Subjects
- Child, Connexin 26, Genes, Recessive, Humans, Polymorphism, Single-Stranded Conformational, Sequence Deletion, Switzerland, White People, Connexins genetics, Hearing Loss genetics, Mutation
- Abstract
Hearing loss is a frequent disease with an estimated incidence of 1:1000 in children. Hereditary hearing loss is characterised by enormous genetic heterogeneity, which makes diagnosis difficult. Approximately 50% of the Caucasian patients with autosomal recessive inherited hearing loss carry mutations in the connexin-26 gene on chromosome 13. Standard screening procedures such as SSCP (single strand conformation polymorphism) analysis, DHPLC (denaturing high performance liquid chromatography) and subsequent sequencing are used to investigate this gene. A genetic test is thus available which can be offered to probands in genetic counselling. We investigated 11 patients with hearing loss and found sequence aberrations in 7 patients, which is causative for the hearing loss in at least 5 patients. The first application of DHPLC in Switzerland is also documented.
- Published
- 2000
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