21 results on '"Lincke CR"'
Search Results
2. Zorg voor het kind met ernstige meervoudige beperkingen
- Author
-
Bindels - de Heus, Karen, Lincke, CR, Derksen - Lubsen, G, and Pediatrics
- Published
- 2011
3. 5q35 duplication syndrome: Narrowing the critical region on the distal side and further evidence of intrafamilial variability and expression.
- Author
-
van der Lugt NM, Weerts MJA, Veenma DCM, Lincke CR, Gischler SJ, Alders M, and van Ierland Y
- Subjects
- Male, Female, Humans, Mothers, Phenotype, Sotos Syndrome genetics, Abnormalities, Multiple genetics, Dwarfism, Microcephaly diagnosis, Microcephaly genetics
- Abstract
The key features of patients with a microduplication 5q35.2q35.3 (including the NSD1 gene) are short stature, microcephaly, mild developmental delay, behavioral problems, digital anomalies and congenital anomalies of internal organs. This core phenotype can be viewed as the reversed phenotype of Sotos syndrome, which is caused by a microdeletion in the same chromosomal region or a pathogenic variant in the NSD1 gene, and includes tall stature and macrocephaly, developmental delay, and epilepsy. Here, we report on a patient and his mother, both with a 5q35.2q35.3 duplication, adding a fifth family to the recently published overview of 39 patients of Quintero-Rivera et al. Our patient had several congenital anomalies, intrauterine growth restriction with a persisting short stature, while his mother was only mildly affected with decreased growth parameters. In addition, he had hemophagogocytic lymphohistiocytosis (HLH) triggered by Haemophilus influenzae and was recently diagnosed with Ewing sarcoma. Our cases carry the smallest duplication published (ca 332 kb, arr[hg19] 5q35.2q35.3(176493106-176824785)x3) further narrowing the distal side of the critical region of the 5q35.2q35.3 duplication. Besides broadening the clinical phenotypic spectrum, our report indicates that the 5q35.2q35.3 microduplication also shows a large intra-familial variability and expression., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
- View/download PDF
4. Treatment Experiences with Intravenous Immunoglobulins, Ixekizumab, Dupilumab, and Anakinra in Netherton Syndrome: A Case Series.
- Author
-
Ragamin A, Nouwen AEM, Dalm VASH, van Mierlo MMF, Lincke CR, and Pasmans SGMA
- Subjects
- Humans, Interleukin 1 Receptor Antagonist Protein therapeutic use, Retrospective Studies, Treatment Outcome, Immunoglobulins, Intravenous therapeutic use, Netherton Syndrome drug therapy
- Abstract
Background: Netherton syndrome (NS) is a rare potential life-threatening disorder that causes severe defects to the skin barrier. No effective treatment options are available for patients with NS and current therapy is mostly supportive. The effects of intravenous immunoglobulins (IVIGs), ixekizumab, and dupilumab have scarcely been reported. Additionally, the role of anakinra in patients with NS has never been investigated., Objectives: The objective was to report our experiences of treatment with IVIG, ixekizumab, dupi-lumab, and anakinra in patients with NS., Methods: A retrospective case series, including 5 patients with NS, was performed in a tertiary referral hospital between 2016 and 2021. Patients were treated with IVIG, ixekizumab, dupilumab, and/or anakinra. Long-term experiences with treatment regimens and adverse events requiring medical attention were reported., Results: IVIG, ixekizumab, dupilumab, and anakinra were well tolerated with no severe adverse events. The 2 patients that received IVIG showed clinical response for 6 months and 2.5 years. Ixekizumab was effective in 1 of our patients for 3.5 years, while in another patient ixekizumab lost its effect after 1.5 years. Dupilumab treatment did not result in persistent improvement of NS-related skin symptoms in 1 patient. Anakinra showed physician-assessed clinical response during the first months of treatment in 4 patients with NS. During anakinra treatment, no changes in blood levels of IL-1β, IL-6, and TNF-α levels were measured at routine blood examinations., Conclusions: This case series suggests that the use of IVIG, ixekizumab, dupilumab, and anakinra in NS is safe and moderately effective on the short term. On the long term, a decline in effect was observed. Our experiences may help clinicians and researchers to provide adequate care and develop treatment for these severely affected patients. More international research, especially on the long term, is needed to determine if and which patients benefit most from the emerging therapies for NS., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2023
- Full Text
- View/download PDF
5. [Genome-wide diagnostics; after the results the real work begins].
- Author
-
Bannink N, Joosten M, Brooks AS, and Lincke CR
- Subjects
- Abnormalities, Multiple genetics, Child, Female, Humans, Abnormalities, Multiple diagnosis, Genetic Testing methods, Ribs abnormalities, Spine abnormalities, Exome Sequencing methods
- Abstract
Introduction of new genetic test technologies in the last decade have accelerated genetic diagnosis in many medical specialties and have increased diagnostic yield considerably. SNP-arrays have been established as first tier diagnostic tools, more and more being replaced by next generation sequencing strategies, like targeted genomic panels and whole exome sequencing. We present the diagnostic work-up of a clinical case, a girl with congenital vertebral and rib anomalies. This case illustrates the complexity of genetic tests and the need for knowledge and experience to interpret the results. Intensive collaboration between pediatrician, clinical geneticist and laboratory specialist is mandatory, as is long-term commitment to involve parents in the diagnostic journey .
- Published
- 2021
6. Care for children with severe chronic skin diseases.
- Author
-
De Maeseneer H, Van Gysel D, De Schepper S, Lincke CR, Sibbles BJ, Versteegh JJWM, Oei W, Pangalila RF, and Pasmans SGMA
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Chronic Disease psychology, Dermatology standards, Female, Humans, Infant, Male, Parents psychology, Qualitative Research, Quality of Health Care standards, Surveys and Questionnaires, Quality of Life, Skin Diseases psychology
- Abstract
In this study, the care for children with a severe chronic skin disease in our national expert center of pediatric dermatology was evaluated. Patients and their parents were questioned by using existing questionnaires: 50 pediatric patients completed the modified "my positive health" questionnaire of Huber and 51 parents completed Pelentsov parental needs scale. Nineteen involved professionals answered a questionnaire with open boxes. Parents of children with a variety of chronic skin diseases and young adult patients were interviewed to find out what an optimal approach would look like according to them. Children with a severe chronic and/or congenital skin disorder score high on the "my positive health" questionnaire, indicating they are able to adapt and self-manage. Their highest median score was measured for the dimension "quality of life." Their parents expect improvement of "working with health care professionals," more specifically they want them to adopt a more holistic approach throughout the patient's life. Structured interviews showed they expect that a multidisciplinary team of care providers determine together with the patient and its family-in advance-which care is needed, at what time and by whom. The interviewed professionals indicated adoption of a holistic multidisciplinary approach as the single largest improvement to achieve better care.Conclusion: Although these children with a severe chronic and/or congenital skin disease were able to adapt and self-manage, they need a more personalized integrative multidisciplinary and systematic transmural approach covering all aspects of life during their lifetime. What is Known: • Severe skin disorders affect the child and its family in several ways. In our expert center, we try to optimize the care for these children through a multidisciplinary approach. What is New: • To our knowledge, no English publication describes the requirements for good care for pediatric patients with severe chronic skin disorders and how to optimize this care. We evaluated the health status of children with severe chronic skin disorders and the strengths and weaknesses of past and current care by questioning these children, their parents, adult patients, and involved professionals.
- Published
- 2019
- Full Text
- View/download PDF
7. [Fragile X syndrome: new therapeutic strategies].
- Author
-
Zeidler S, Dierckx B, Lubbers K, van Eeghen AM, Lincke CR, Kievit JA, Willemsen R, and Rietman A
- Subjects
- Animals, Autism Spectrum Disorder, Child, Clinical Trials as Topic, Humans, Intellectual Disability, Disease Models, Animal, Fragile X Syndrome genetics, Fragile X Syndrome therapy, Molecular Targeted Therapy
- Abstract
Background: Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy.
AIM: To present an overview of the development of targeted treatment for fxs.
METHOD: Several important publications were collected and indexed.
RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing.
CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement future therapeutic strategies and to facilitate research. In addition, this improves patient care, one example being the recent medical guideline for children with fxs.- Published
- 2018
8. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
- Author
-
Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, Brunt ER, Peeters EA, Gómez Garcia EB, van der Knaap MS, Lincke CR, Laan LA, Tijssen MA, van Rijn MA, Majoor-Krakauer D, Visser M, van 't Veer LJ, Kleijer WJ, van de Warrenburg BP, Warris A, de Groot IJ, de Groot R, Broeks A, Preijers F, Kremer BH, Weemaes CM, Taylor MA, van Deuren M, and Willemsen MA
- Subjects
- Adolescent, Adult, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Child, DNA-Binding Proteins genetics, Female, Genetic Association Studies, Humans, Male, Middle Aged, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins genetics, Young Adult, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia pathology, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk., (© 2011 Wiley Periodicals, Inc.)
- Published
- 2012
- Full Text
- View/download PDF
9. Recombinant human deoxyribonuclease in infants with respiratory syncytial virus bronchiolitis.
- Author
-
Boogaard R, Hulsmann AR, van Veen L, Vaessen-Verberne AAPH, Yap YN, Sprij AJ, Brinkhorst G, Sibbles B, Hendriks T, Feith SWW, Lincke CR, Brandsma AE, Brand PLP, Hop WCJ, de Hoog M, and Merkus PJFM
- Subjects
- Administration, Inhalation, Double-Blind Method, Expectorants adverse effects, Female, Follow-Up Studies, Humans, Infant, Intensive Care Units, Pediatric, Length of Stay, Male, Oxygen Inhalation Therapy, Patient Admission, Bronchiolitis drug therapy, Deoxyribonuclease I administration & dosage, Expectorants administration & dosage, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus, Human drug effects
- Abstract
Background: Treatment of hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis is mainly supportive. Bronchodilators and systemic steroids are often used but do not reduce the length of hospital stay. Because hypoxia and airways obstruction develop secondary to viscous mucus in infants with RSV bronchiolitis, and because free DNA is present in RSV mucus, we tested the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase)., Methods: In a multicenter, randomized, double-blind, controlled clinical trial, 225 oxygen-dependent infants admitted to the hospital for RSV bronchiolitis were randomly assigned to receive 2.5 mg bid of nebulized rhDNase or placebo until discharge. The primary end point was length of hospital stay. Secondary end points were duration of supplemental oxygen, improvement in symptom score, and number of intensive care admissions., Results: There were no significant differences between the groups with regard to the length of hospital stay (p = 0.19) or the duration of supplemental oxygen (p = 0.07). The ratio (rhDNase/placebo) of geometric means of length of stay was 1.12 (95% confidence interval, 0.96 to 1.33); for the duration of supplemental oxygen, the ratio was 1.28 (95% confidence interval, 0.97 to 1.68). There were no significant differences in the rate of improvement of the symptom score or in the number of intensive care admissions., Conclusions: Administration of rhDNase did not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.
- Published
- 2007
- Full Text
- View/download PDF
10. [Diagnosis image (262). A newborn baby with unilatreral ptosis].
- Author
-
Nout E and Lincke CR
- Subjects
- Blepharoptosis pathology, Blepharoptosis surgery, Female, Humans, Infant, Newborn, Blepharoptosis congenital, Blepharoptosis diagnosis, Eyelids innervation, Facial Muscles innervation, Jaw innervation
- Abstract
A newborn girl was seen with one eye closed, which she opened synchronous with suction; this was due to a congenital ptosis, so-called Marcus Gunn jaw-winking ptosis.
- Published
- 2006
11. Quality of evidence-based pediatric guidelines.
- Author
-
Boluyt N, Lincke CR, and Offringa M
- Subjects
- Child, Humans, Infant, Newborn, Quality Control, Evidence-Based Medicine, Pediatrics standards, Practice Guidelines as Topic standards
- Abstract
Objective: To identify evidence-based pediatric guidelines and to assess their quality., Methods: We searched Medline, Embase, and relevant Web sites of guideline development programs and national pediatric societies to identify evidence-based pediatric guidelines. A list with titles of identified guidelines was sent to 51 leading pediatricians in the Netherlands, who were asked to select the 5 most urgent topics for guideline development. Three pediatrician reviewers appraised the available guidelines on the 10 most frequently mentioned topics with the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument., Results: A total of 215 evidence-based pediatric guidelines were identified; of these, 17 guidelines on the 10 most frequently mentioned topics were appraised. The AGREE instrument rates guidelines among 6 domains. For the scope and purpose domain, the mean score was 84% of the maximal mark. For stakeholder involvement, the mean score was 42%, with 12 guidelines (71%) scoring <50%. For rigor of development, the mean score was 54%, with 5 guidelines (29%) scoring <50%. For clarity and presentation, the mean score was 78%, with 4 guidelines (24%) scoring <50%. For applicability and editorial independence, performance was poor, with mean scores of 19% and 40%, respectively. Low scores were partly attributable to poor reporting. After considering all domain scores, the reviewers recommended 14 of 17 guidelines (82%) to be used in local practice., Conclusions: The current volume of pediatric guidelines categorized as evidence based in popular databases is large. Overall, these guidelines scored well, compared with other studies on guideline quality in fields outside pediatrics, when assessed for quality with the AGREE instrument. This holds especially for guidelines published or endorsed by the American Academy of Pediatrics or registered in the National Guideline Clearinghouse.
- Published
- 2005
- Full Text
- View/download PDF
12. Cerebellar hypoplasia in respiratory chain dysfunction.
- Author
-
Lincke CR, van den Bogert C, Nijtmans LG, Wanders RJ, Tamminga P, and Barth PG
- Subjects
- Consanguinity, Fatal Outcome, Female, Humans, Infant, Newborn, Lactic Acid cerebrospinal fluid, Magnetic Resonance Imaging, Morocco, Muscle Hypotonia enzymology, Cerebellum abnormalities, Cytochrome-c Oxidase Deficiency, Mitochondrial Encephalomyopathies diagnosis
- Abstract
Disruption of early or late fetal brain development resulting in structural abnormalities may be associated with inborn errors of mitochondrial metabolism. It is common in patients with deficiency of pyruvate dehydrogenase activity and it has sporadically been described in patients with dysfunction of the tricarboxylic acid cycle. Mitochondrial respiratory chain disorders are not commonly known to interfere with early brain development. We describe here a girl with an encephalomyopathy likely to be due to a novel type of deficiency of cytochrome c oxidase (complex IV) activity that presented with severe hypotonia, myoclonic seizures, optic atrophy and elevated lactate concentration in cerebrospinal fluid shortly after birth. Cranial magnetic resonance imaging revealed hypoplasia of the cerebellum with rudimentary cerebellar hemispheres and relative sparing of the vermis. This case suggests that deficiency of cytochrome c oxidase and possibly respiratory chain disorders in general have to be considered in the differential diagnosis of cerebellar hypoplasia.
- Published
- 1996
- Full Text
- View/download PDF
13. Altered kinetics of cytochrome c oxidase in a patient with severe mitochondrial encephalomyopathy.
- Author
-
Nijtmans LG, Barth PG, Lincke CR, Van Galen MJ, Zwart R, Klement P, Bolhuis PA, Ruitenbeek W, Wanders RJ, and Van den Bogert C
- Subjects
- Cells, Cultured, Consanguinity, Electron Transport Complex IV chemistry, Electron Transport Complex IV genetics, Female, Fibroblasts enzymology, Humans, Infant, Newborn, Kinetics, Mitochondrial Encephalomyopathies genetics, Mutation, Protein Conformation, Cytochrome-c Oxidase Deficiency, Mitochondrial Encephalomyopathies enzymology
- Abstract
Deficiency of cytochrome c oxidase activity was established in a girl born to consanguineous parents. She showed symptoms of dysmaturity, generalized hypotonia, myoclonic seizures and progressive respiratory failure, leading to death on the seventh day of life. Structural abnormalities of the central nervous system consisted of severe cerebellar hypoplasia and optic nerve atrophy. Biochemical analysis of a muscle biopsy specimen demonstrated deficiency of cytochrome c oxidase activity. Cultured fibroblasts from this patient also showed a selective decrease in the activity of cytochrome c oxidase, excluding a muscle-specific type of deficiency. Further investigations in cultured fibroblasts revealed that synthesis, assembly and stability of both the mitochondrial and the nuclear subunits of the enzyme were entirely normal. The steady-state concentration of cytochrome c oxidase in the fibroblasts of the patient was also normal, suggesting that the kinetic properties of the enzyme were altered. Analysis of the kinetic parameters of cytochrome c oxidase demonstrated an aberrant interaction between cytochrome c oxidase and its substrate, cytochrome c, most likely because of a mutation in one of the nuclear subunits of the enzyme.
- Published
- 1995
- Full Text
- View/download PDF
14. Tissue distribution of the human MDR3 P-glycoprotein.
- Author
-
Smit JJ, Schinkel AH, Mol CA, Majoor D, Mooi WJ, Jongsma AP, Lincke CR, and Borst P
- Subjects
- Amino Acid Sequence, Animals, Gene Expression, Humans, Immunoenzyme Techniques, In Vitro Techniques, Mice, Mice, Knockout, Molecular Sequence Data, Peptides chemistry, RNA, Messenger genetics, Recombinant Fusion Proteins immunology, Tissue Distribution, Tumor Cells, Cultured, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Drug Resistance, Multiple
- Abstract
Background: P-glycoproteins (Pgps) belong to a family of well conserved plasma membrane proteins with two members in humans: MDR1 and MDR3. The MDR1 Pgp can transport drugs; the murine homologue of MDR3, mdr2, was recently shown by us to be involved in transport of the phospholipid phosphatidylcholine (lecithin) into bile., Experimental Design: We have determined the MDR3 mRNA levels in a panel of human tissues by RNase protection. We have also generated polyclonal antibodies specific for the MDR3 Pgp. Detection of the MDR3 Pgp in human tissues with these antibodies was by a streptavidin-ABC procedure., Results: The RNase protection results show that expression of the MDR3 gene has a more restricted distribution than that of MDR1. A high level of MDR3 mRNA was detected in the liver and in low levels in the adrenal gland, heart, striated muscle, spleen, and tonsil. In all of these tissues, some of the previously described splice variants of MDR3 were abundantly expressed. No indications were found for a tissue-specific regulation of alternative splicing of the MDR3 pre-mRNA. Two MDR3 Pgp-specific antibodies stained the bile canalicular membrane of hepatocytes across the entire liver lobule. No staining was found in the epithelial cells of the bile ductules and gall bladder, indicating that the staining at these sites with C219, a monoclonal antibody that recognizes both MDR1 and MDR3 Pgp, (mainly) represents the MDR1 Pgp. No MDR3 was detected by specific antibodies in the adrenal gland, spleen, and muscle. Since no staining was reported with MDR1-specific antibodies in muscle either, our results indicate that the C219 staining in some fibers of striated muscle represents a cross-reaction with another protein. One of the human MDR3-specific antibodies cross-reacted with the highly homologous mouse mdr2 Pgp. Staining with this antibody showed that the distribution of this protein in mouse liver and striated muscle is very similar to that of MDR3 Pgp in human tissues., Conclusions: The highest expression of the MDR3 Pgp was found in liver in the canalicular membranes of hepatocytes. This is in agreement with a role for MDR3 in the transport of phospholipid into bile.
- Published
- 1994
15. The expression of two P-glycoprotein (pgp) genes in transgenic Caenorhabditis elegans is confined to intestinal cells.
- Author
-
Lincke CR, Broeks A, The I, Plasterk RH, and Borst P
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Animals, Genetically Modified, Caenorhabditis growth & development, Drug Resistance, Gene Expression, Genes, Intestinal Mucosa metabolism, Promoter Regions, Genetic, RNA, Messenger genetics, Recombinant Fusion Proteins genetics, Caenorhabditis genetics, Membrane Glycoproteins genetics
- Abstract
P-glycoproteins can cause multidrug resistance in mammalian tumor cells by active extrusion of cytotoxic drugs. The natural function of these evolutionarily conserved, membrane-bound ATP binding transport proteins is unknown. In mammals, P-glycoproteins are abundantly present in organs associated with the digestive tract. We have studied the tissue-specific expression of Caenorhabditis elegans P-glycoprotein genes pgp-1 and pgp-3 by transformation of nematodes with pgp-lacZ gene fusion constructs in which the promoter area of the pgp genes was fused to the coding region of lacZ. Expression of pgp-1 and pgp-3, as inferred from pgp-lacZ transgenic nematodes, was confined to the intestinal cells. The expression patterns of both genes were virtually indistinguishable. Quantitative analysis of pgp mRNA levels during development showed that pgp-1, -2, and -3 were expressed throughout the life cycle of C.elegans, albeit with some variation indicating developmental regulation. The expression of P-glycoprotein genes in intestinal cells is an evolutionarily conserved feature of these genes, consistent with the hypothesis that P-glycoproteins provide a mechanism of protection against environmental toxins.
- Published
- 1993
- Full Text
- View/download PDF
16. The P-glycoprotein gene family of Caenorhabditis elegans. Cloning and characterization of genomic and complementary DNA sequences.
- Author
-
Lincke CR, The I, van Groenigen M, and Borst P
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1, Amino Acid Sequence, Animals, Base Sequence, Biological Evolution, Caenorhabditis elegans, Cloning, Molecular, DNA, Single-Stranded, Genetic Complementation Test, Humans, Molecular Sequence Data, RNA Splicing, Restriction Mapping, Sequence Homology, Amino Acid, Transcription, Genetic, Membrane Glycoproteins genetics, Multigene Family
- Abstract
P-glycoproteins, encoded by families of evolutionarily conserved genes, can confer a multidrug-resistant phenotype to mammalian tumor cells. To obtain more information on their functions in normal cells we have cloned genomic and complementary DNA sequences of four P-glycoprotein gene homologs of the genetically well-characterized nematode Caenorhabditis elegans, termed pgp-1, pgp-2, pgp-3 and pgp-4, respectively. The genes were physically mapped on chromosome IV (pgp-1), I (pgp-2) and X (pgp-3 and pgp-4). Phenotypic mutants corresponding to these loci have not yet been described. Two of the genes, pgp-1 and pgp-3, were analyzed in detail. They are predicted to encode ATP-binding membrane-spanning proteins of 1321 and 1254 amino acid residues, respectively, with the characteristic features shared by most P-glycoproteins described thus far. Intra-species divergence of P-glycoprotein genes is more pronounced in C. elegans than in mammals. Only 40% of the amino acids of pgp-1 and pgp-3 are identical, in contrast to 77% identity between human MDR1 and MDR3. pgp-1 consists of 14 exons, pgp-3 of 13. The two genes share only one intron position, whereas they share four (pgp-1) and five (pgp-3) intron positions with mammalian P-glycoprotein genes. pgp-1, pgp-2, and pgp-3 are transcribed into low abundance mRNAs in wild-type nematodes. pgp-1 and pgp-3 mRNAs have the trans-spliced leader SL1 at their 5' ends. Arsenite, emetine and actinomycin D drugs did not increase the steady state levels of pgp mRNA, unlike in some mammalian cell types. Heat shock disturbed trans as well as cis-splicing of pgp-1 and led to the accumulation of partially processed pgp-1 RNA. Thus, in C. elegans these genes are not induced in the context of a general stress response, as has been proposed for mammalian P-glycoprotein genes in certain tissues.
- Published
- 1992
- Full Text
- View/download PDF
17. Structure of the human MDR3 gene and physical mapping of the human MDR locus.
- Author
-
Lincke CR, Smit JJ, van der Velde-Koerts T, and Borst P
- Subjects
- Amino Acid Sequence, Base Sequence, Blotting, Southern, Electrophoresis, Agar Gel, Exons, Glycoproteins genetics, Humans, Introns, Methylation, Molecular Sequence Data, Sequence Alignment, Transcription, Genetic, Drug Resistance genetics, Restriction Mapping
- Abstract
Two genes, MDR1 and MDR3, constitute the human P-glycoprotein gene family. To examine the evolutionary relationship between the three known classes of mammalian P-glycoprotein genes, we have cloned the MDR3 gene and compared its structure with that of the human MDR1 and the mouse mdr1 (mdr1b) genes analyzed by other groups. The MDR3 gene contains 28 exons and 27 of these contain coding sequences for the two homologous halves of the protein that correlate with functional domains. This structure is virtually identical to that of the human MDR1 gene and the mouse mdr1 (mdr1b) gene, indicating that the exon/intron structure was fixed before the duplication events that generated different classes of P-glycoproteins, but after the P-glycoproteins diverged from related genes, like the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which has an entirely different exon/intron structure. The four alternatively spliced transcripts of the MDR3 gene arise from alternative splicing of exons 23 and 26. Our analysis of DNA clones covering about 120 kilobases (kb) of the human MDR locus, including the entire MDR3 gene (74 kb) and the intergenic region between both genes (34 kb), combined with pulsed-field gel electrophoresis data shows that the human MDR locus covers about 230 kb. In contrast to the mouse mdr genes, both human genes are transcribed in the same direction (MDR3 located downstream of MDR1). The CpG-rich sequences marking the 5' ends of both genes are hypomethylated to different extents in different cell lines. Hypomethylation roughly correlates with transcriptional activity.
- Published
- 1991
18. Resistance to natural products in leukemia.
- Author
-
Borst P, Baas F, Lincke CR, Schinkel AH, Smit JJ, and Van der Velde-Koerts T
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Carrier Proteins genetics, Carrier Proteins metabolism, Gene Expression, Humans, Leukemia genetics, Leukemia metabolism, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, RNA Splicing, Drug Resistance genetics, Leukemia drug therapy
- Published
- 1990
19. Multidrug resistance phenotype of human BRO melanoma cells transfected with a wild-type human mdr1 complementary DNA.
- Author
-
Lincke CR, van der Bliek AM, Schuurhuis GJ, van der Velde-Koerts T, Smit JJ, and Borst P
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1, Biological Transport, Cell Division drug effects, Cell Line, Cell Membrane metabolism, DNA genetics, Daunorubicin metabolism, Humans, Kinetics, Melanoma, Nucleic Acid Hybridization, Phenotype, Tumor Cells, Cultured cytology, Tumor Cells, Cultured metabolism, Antineoplastic Agents pharmacology, Drug Resistance genetics, Membrane Glycoproteins genetics, Transfection, Tumor Cells, Cultured drug effects
- Abstract
We have transfected a eukaryotic expression vector containing a mdr1 complementary DNA isolated from normal human liver into human BRO melanoma cells to study the drug-resistant phenotype produced by the exclusive overexpression of normal human mdr1 P-glycoprotein. The drug resistance pattern of mdr1-transfected clones includes relatively high resistance to gramicidin D (about 300-fold), vincristine (about 100-fold), and actinomycin D (about 100-fold) and a lower degree of resistance to doxorubicin (about 10-fold), VP16-213 (about 10-fold), and colchicine (about 6-fold). The transfectants did not exhibit resistance to trimetrexate, cis-platinum, mitomycin C, 1-beta-D-arabinofuranosylcytosine, bleomycin, G418, or magainin-2-amide; they were slightly more sensitive to verapamil (2-fold) but not to Triton X-100. As in other multidrug-resistant cell lines, resistance to vincristine could be reversed by verapamil and, more effectively, by cyclosporin A. Chloroquine only marginally increased drug sensitivity in mdr1-transfected cells. Gramicidin D resistance was also reversed by verapamil, suggesting that the mechanism of resistance to this polypeptide antibiotic is similar to that of other drugs transported by P-glycoprotein. Thus, expression of the wild-type mdr1 complementary DNA induces a drug-resistant phenotype similar to that induced by mdr1 complementary DNAs isolated from drug-resistant cell lines with relatively low colchicine resistance. As other cell lines may display a different pattern of drug resistance, it is clear that other resistance mechanisms or cell type-specific factors may modulate the resistance. mdr1-transfected cell lines provide a convenient tool for the identification of P-glycoprotein-mediated phenomena.
- Published
- 1990
20. Circular DNA of 3T6R50 double minute chromosomes.
- Author
-
van der Bliek AM, Lincke CR, and Borst P
- Subjects
- Animals, Cell Line, DNA, Bacterial analysis, DNA, Bacterial radiation effects, DNA, Circular radiation effects, Drug Resistance, Electrophoresis, Agar Gel methods, Escherichia coli analysis, Gamma Rays, Methotrexate pharmacology, Mice, Mycoplasma analysis, DNA, Circular analysis, Gene Amplification
- Abstract
In pulsed field gradient gel electrophoresis (PFGE) the intact deproteinized circular DNA of Mycoplasma (800 kb) and Escherichia coli (4700 kb) remains trapped in the slot. We show here that gamma-irradiation of the DNA in agarose plugs is a convenient method to partially convert these circles into full-length linears, migrating with the expected mobility in PFGE. We have used this method to study the structure of Double Minute chromosomes (DMs) from the methotrexate (MTX)-resistant mouse cell line 3T6R50. Intact deproteinized DM DNA is immobile in these gels, but is converted into a single band of about 2500 kb by either gamma-irradiation, DNaseI in the presence of Mn2+, or restriction enzymes. We conclude that the DM DNA in 3T6R50 cells consists of a homogeneous population of 2500-kb circles.
- Published
- 1988
- Full Text
- View/download PDF
21. Growth of chromosome ends in multiplying trypanosomes.
- Author
-
Bernards A, Michels PA, Lincke CR, and Borst P
- Subjects
- Animals, Base Sequence, DNA Restriction Enzymes, Genes, Genetic Variation, Glycoproteins genetics, Nucleic Acid Hybridization, Trypanosoma genetics, Chromosomes physiology, DNA Replication, Trypanosoma physiology
- Abstract
Some of the genes for the variant surface glycoproteins of trypanosomes are located close to a discontinuity in the DNA, presumably a chromosome end. We show here that DNA fragments containing these telomeres increase in length in multiplying trypanosomes at a rate of about 10 base pairs per division. We argue that chromosome growth may not be restricted to trypanosomes and could explain the heterogeneity of telomeric DNA fragments observed in some other organisms.
- Published
- 1983
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.