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1.
Br J Cancer ; 112(5): 851-6, 2015 Mar 03.
Article in English | MEDLINE | ID: mdl-25668003

ABSTRACT

BACKGROUND: Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity. METHODS: The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20). RESULTS: High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04). CONCLUSIONS: Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/therapy , Hyperthermia, Induced/methods , Mitomycin/pharmacology , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/therapy , Antibiotics, Antineoplastic/therapeutic use , Caco-2 Cells , Cell Line, Tumor , Colorectal Neoplasms/mortality , Fanconi Anemia Complementation Group D2 Protein/metabolism , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , HT29 Cells , Humans , Mitomycin/therapeutic use , Peritoneal Neoplasms/mortality , RecQ Helicases/metabolism , Signal Transduction/drug effects , Survival Analysis , Translational Research, Biomedical
2.
Arch Dis Child ; 95(12): 974-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20736400

ABSTRACT

BACKGROUND: Rectal measurement is considered a gold standard in many healthcare systems for body temperature measurement in children. Although this method has several disadvantages, an ideal alternative thermometer has not yet been introduced. However tympanic and infrared skin thermometers are potential alternatives. METHODS: A prospective cohort study was performed including 100 children between 0 and 18 years of age admitted to the general paediatric ward of Spaarne Hospital in The Netherlands between January and March 2009. The objectives of this study are to evaluate the accuracy of tympanic and two types of infrared skin thermometers (Beurer and Thermofocus) compared to rectal measurement and furthermore to evaluate the influence of different variables on temperature measurements. RESULTS: Compared to rectal measurement (37.56°C), the mean temperatures of the tympanic (37.29°C), Beurer (36.79°C) and Thermofocus (37.30°C) thermometers differed significantly (p<0.001). Mean and SD of differences between rectal temperature and temperature measured with these alternative devices varied significantly (p<0.001). Sensitivity, specificity, positive and negative predictive values for detecting rectal fever measured with the tympanic, Beurer and Thermofocus thermometers are unacceptable, especially for the Beurer thermometer. This difference in temperature between rectal and the alternative thermometers remained after stratification on gender, age, skin colour and otoscopic abnormalities. CONCLUSIONS: In this study the authors demonstrated that the tympanic, Beurer and Thermofocus thermometers cannot reliably predict rectal temperature. Therefore the authors do not advise replacement of rectal measurement as the gold standard for detecting fever in children by one of these devices. When rectal measurement is not used, the infrared skin thermometers appear to perform less well than tympanic measurements.


Subject(s)
Body Temperature/physiology , Thermometers , Tympanic Membrane/physiology , Adolescent , Age Factors , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Infrared Rays , Prospective Studies , Rectum/physiology , Reproducibility of Results , Sex Factors , Skin Pigmentation/physiology , Skin Temperature/physiology
3.
Ned Tijdschr Geneeskd ; 152(8): 413-7, 2008 Feb 23.
Article in Dutch | MEDLINE | ID: mdl-18361186

ABSTRACT

During the summer of 2006 in the paediatric ward of the Spaarne Hospital in Hoofddorp, the Netherlands, a large number of children were admitted with a coxsackievirus type-B infection, one of the enteroviruses. A total of 27 children were diagnosed with this virus. Patient A, a one-month-old boy, was admitted with fever. The spinal fluid showed a high leukocyte count. He was treated with amoxicillin, ceftriaxon and acyclovir, and recovered rapidly. The spinal fluid culture was positive for coxsackievirus type B5. Patient B, a 3-year-old girl, presented with attacks of abdominal pain and groaning respiration. Infection parameters were mildly elevated. The chest X-ray was normal. She was admitted for observation and recovered spontaneously. Viral faeces culture revealed coxsackievirus type B4. Rapid recognition of an enterovirus infection is important to prevent unnecessary diagnostic and therapeutic interventions. PCR is a diagnostic technique of great importance.


Subject(s)
Antiviral Agents/therapeutic use , Coxsackievirus Infections/epidemiology , Disease Outbreaks/veterinary , Enterovirus B, Human/isolation & purification , Child, Preschool , Coxsackievirus Infections/diagnosis , Coxsackievirus Infections/drug therapy , Female , Humans , Infant, Newborn , Male , Netherlands , Polymerase Chain Reaction/methods , Treatment Outcome
4.
Ned Tijdschr Geneeskd ; 150(48): 2625-9, 2006 Dec 02.
Article in Dutch | MEDLINE | ID: mdl-17205936

ABSTRACT

Three healthy boys, 3.5, 5 and 1.5 years of age, were admitted to hospital with a severe bacterial skin infection, cerebellar ataxia, and pneumonia, respectively, one week after the onset of varicella. They recovered completely after treatment. Studies in Europe report complications from varicella in 2.5% of healthy children. Most of these are neurological complications and secondary bacterial infections of skin and soft tissue. Last year, a European consensus was published that recommended that all healthy children be vaccinated against chickenpox. In The Netherlands, routine varicella zoster virus (VZV) vaccination has not (yet) been implemented. We propose a new discussion on the possible inclusion of VZV vaccination in the national vaccination programme.


Subject(s)
Cerebellar Ataxia/etiology , Chickenpox Vaccine , Chickenpox/complications , Herpesvirus 3, Human/immunology , Pleuropneumonia/etiology , Skin Diseases, Bacterial/etiology , Cerebellar Ataxia/epidemiology , Chickenpox/prevention & control , Child, Preschool , Health Policy , Humans , Immunization Programs , Infant , Male , Netherlands/epidemiology , Pleuropneumonia/epidemiology , Skin Diseases, Bacterial/epidemiology
6.
Eur J Hum Genet ; 8(11): 861-8, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11093276

ABSTRACT

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families - 97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.


Subject(s)
DNA-Binding Proteins/genetics , Fanconi Anemia/genetics , Mutation , Amino Acid Sequence , Base Sequence , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Fanconi Anemia Complementation Group G Protein , Humans , Molecular Sequence Data , Polymorphism, Single-Stranded Conformational , Sequence Homology, Amino Acid
7.
Hum Mol Genet ; 9(18): 2665-74, 2000 Nov 01.
Article in English | MEDLINE | ID: mdl-11063725

ABSTRACT

Fanconi anemia (FA) is a chromosomal instability syndrome associated with a strong predisposition to cancer, particularly acute myeloid leukemia and squamous cell carcinoma. At the cellular level, FA is characterized by spontaneous chromosomal breakage and a unique hypersensitivity to DNA cross-linking agents. Complementation analysis has indicated that at least seven distinct genes are involved in the pathogenesis of FA. Despite the identification of four of these genes (FANCA, FANCC, FANCF and FANCG), the nature of the 'FA pathway' has remained enigmatic, as the FA proteins lack sequence homologies or motifs that could point to a molecular function. To further define this pathway, we studied the subcellular localizations and mutual interactions of the FA proteins, including the recently identified FANCF protein, in human lymphoblasts. FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. These interactions were detected in wild-type and FA-D lymphoblasts, but not in lymphoblasts of other FA complementation groups. This implies that each of the FA proteins, except FANCD, is required for these complexes to form. Similarly, we show that the interaction between FANCA and FANCC is restricted to wild-type and FA-D cells. Furthermore, we document the subcellular localization of FANCA and the FANCA/FANCG complex in all FA complementation groups. Our results, along with published data, culminate in a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity.


Subject(s)
Cell Cycle Proteins , Cell Nucleus/chemistry , DNA-Binding Proteins/metabolism , Fanconi Anemia/metabolism , Proteins/metabolism , RNA-Binding Proteins/metabolism , Antibody Specificity , Blotting, Western , Cell Nucleus/metabolism , Cytoplasm/chemistry , Cytoplasm/metabolism , DNA-Binding Proteins/genetics , Fanconi Anemia/genetics , Fanconi Anemia Complementation Group A Protein , Fanconi Anemia Complementation Group C Protein , Fanconi Anemia Complementation Group F Protein , Fanconi Anemia Complementation Group G Protein , Fanconi Anemia Complementation Group Proteins , Genetic Complementation Test , Humans , Lymphocytes/metabolism , Lymphocytes/pathology , Macromolecular Substances , Models, Biological , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Precipitin Tests , Protein Binding , Protein Biosynthesis , Proteins/genetics , RNA-Binding Proteins/genetics
8.
Biometrics ; 56(3): 808-14, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10985220

ABSTRACT

This paper considers methods for estimating the relationship between a binary response Y and the genetic effects responsible for a second binary trait Z. The responses Y are observed only for target individuals, and the responses Z are observed only for the relatives of these targets. The analysis consists of two parts. The first part concerns the analysis of the family data Z and the second part estimates the relation between the genetic effects and Y. For the family data, a generalized linear mixed model with a logit link and Gaussian genetic (random) effects is used. Estimates of the variances of the genetic effects are obtained by using a pseudo-profile log-likelihood method. Estimation of the log likelihood involves averaging over n-dimensional normal distributions, which is done by importance sampling. The methods used in the second part are straightforward. The methods are applied to a data set containing chronic lung disease (CLDN) responses of newborns and asthma (AS), allergy (AL), chronic bronchitis (CB) and eczema (EC) responses observed for the relatives of these newborns. The clinical question is whether genetic effects of AS, AL, CB, and EC have an effect on the risk for CLDN. It can be concluded that for AS, AL, CB, and EC, the influence of genetic effects is significant. However, these genetic predispositions have no significant effect on CLDN.


Subject(s)
Lung Diseases/genetics , Models, Genetic , Models, Statistical , Respiratory Tract Diseases/genetics , Asthma/epidemiology , Asthma/genetics , Bronchitis/epidemiology , Bronchitis/genetics , Chronic Disease , Eczema/epidemiology , Eczema/genetics , Family , Female , Humans , Hypersensitivity/epidemiology , Hypersensitivity/genetics , Infant, Newborn , Likelihood Functions , Lung Diseases/epidemiology , Male , Normal Distribution , Respiratory Tract Diseases/epidemiology
9.
Am J Hum Genet ; 67(5): 1306-8, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11001585

ABSTRACT

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome with at least seven different complementation groups. Four FA genes (FANCA, FANCC, FANCF, and FANCG) have been identified, and two other FA genes (FANCD and FANCE) have been mapped. Here we report the identification, by complementation cloning, of the gene mutated in FA complementation group E (FANCE). FANCE has 10 exons and encodes a novel 536-amino acid protein with two potential nuclear localization signals.


Subject(s)
Fanconi Anemia/genetics , Genetic Complementation Test , Mutation/genetics , Nuclear Proteins/genetics , Alternative Splicing/genetics , Amino Acid Sequence , Bangladesh/ethnology , Cloning, Molecular , DNA, Complementary/genetics , Exons/genetics , Fanconi Anemia Complementation Group E Protein , Humans , Introns/genetics , Molecular Sequence Data , Nuclear Localization Signals , Nuclear Proteins/chemistry , Turkey/ethnology
10.
Hum Mutat ; 15(6): 578, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10862090

ABSTRACT

Homozygosity for a frameshift mutation at codon 1213 of FANCA gene was identified in a Turkish patient. Immunoprecipitation-western blot analysis showed the complete absence of the FANCA protein band. This novel mutation, a deletion of T at position 3639 in exon 37 (3639delT), is responsible for the disease and causes premature termination of translation 32 aa downstream. The deletion is (i) the T residue of 2 overlapping TGAGGC and CCTG hot spot motifs, (ii) flanked by several direct repeats, (iii) surrounded by the highly GC rich region that have frequently been identified at the site of human DNA deletions. The patient is the third living child of a first degree cousin marriage. The major abnormalities of the patient at the age of 6 months were growth retardation, microcephaly, hypoplastic right thumb, distal displacements of both thumbs and pelvic displacement of left kidney. Hematological presentation of the disease started before the age of 4 years.


Subject(s)
Cell Cycle Proteins , DNA-Binding Proteins , Fanconi Anemia/genetics , Frameshift Mutation/genetics , Nuclear Proteins , Proteins/genetics , Child , Child, Preschool , Codon/genetics , Fanconi Anemia/pathology , Fanconi Anemia Complementation Group Proteins , Female , Humans , Infant
11.
Br J Haematol ; 111(4): 1057-64, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11167740

ABSTRACT

Fanconi anaemia (FA) is an autosomal recessive disease strongly predisposing to bone marrow failure and acute myeloid leukaemia (AML). Four FA genes, corresponding to complementation groups A, C, F and G, have been cloned, but the molecular functions of the corresponding proteins are unknown. The high risk of AML in FA patients suggests that the 'FA pathway' helps to prevent AML in non-FA individuals. We examined 10 AML cell lines, as well as primary cells from 15 AML patients representing the French-American-British subclasses M1-M5a, for possible deficiencies in the 'FA pathway'. Cellular lysates were analysed for the presence of the FA proteins FANCA, FANCC, FANCF and FANCG, as well as the complexes reported to be formed between these proteins, using immunoprecipitation and Western blot analysis. Aberrant protein profiles were observed in five of the 10 cell lines and in 11 of the 15 primary AML samples. Aberrations, that included absence or reduced presence of FA proteins and/or their complexes, were noted in the subclasses M1-M4, but not in M5a (n = 3). Our results suggest that a significant proportion of general AML is characterized by a disturbance of the 'FA pathway' that may represent an early event in the development of this type of leukaemia.


Subject(s)
Cell Cycle Proteins , DNA-Binding Proteins/analysis , Fanconi Anemia/metabolism , Leukemia, Myeloid/metabolism , Nuclear Proteins , Proteins/analysis , RNA-Binding Proteins/analysis , Acute Disease , Adult , Blotting, Western/methods , Bone Marrow Cells/metabolism , Fanconi Anemia Complementation Group A Protein , Fanconi Anemia Complementation Group C Protein , Fanconi Anemia Complementation Group F Protein , Fanconi Anemia Complementation Group G Protein , Fanconi Anemia Complementation Group Proteins , Female , Genetic Predisposition to Disease , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myelomonocytic, Acute/metabolism , Leukemia, Promyelocytic, Acute/metabolism , Male , Middle Aged , Precipitin Tests/methods , Tumor Cells, Cultured
12.
Am J Perinatol ; 17(7): 377-84, 2000.
Article in English | MEDLINE | ID: mdl-12141525

ABSTRACT

Individual lung development during the first year of life was studied in surfactant treated preterm infants with respiratory distress syndrome (RDS) and healthy controls, as well as in a group who subsequently developed chronic lung disease of the newborn (CLDN). Lung development was assessed from functional residual capacity (FRC) and compliance of the respiratory system (Crs). Twenty-one infants with RDS after preterm birth received surfactant treatment. Six of them developed CLDN. Eighteen preterm infants without RDS served as a control group. Lung function measurements were performed at term age and 4, 8, and 12 months afterwards. FRC was obtained by means of the closed-system helium dilution technique whereas static Crs was obtained by means of the weighted spirometer technique. At term age, FRC was lower in the CLDN group compared with uncomplicated RDS and controls (p < 0.05). No significant differences between groups were found in the development of FRC during the first year of life (p = 0.4). No differences were found in Crs during the first year of life in surfactant treated infants who recovered from uncomplicated RDS and the control group. However, lower values were found in the CLDN group (p < 0.05). We conclude that surfactant treated infants without CLDN have similar lung development during the first year of life as control preterm infants.


Subject(s)
Functional Residual Capacity , Infant, Premature, Diseases/physiopathology , Pulmonary Surfactants/therapeutic use , Respiratory Distress Syndrome, Newborn/physiopathology , Gestational Age , Humans , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/therapy , Respiratory Distress Syndrome, Newborn/therapy , Respiratory Function Tests
14.
Proc Natl Acad Sci U S A ; 96(18): 10320-5, 1999 Aug 31.
Article in English | MEDLINE | ID: mdl-10468606

ABSTRACT

Fanconi anemia (FA) is a recessively inherited disease characterized at the cellular level by spontaneous chromosomal instability and specific hypersensitivity to cross-linking agents. FA is genetically heterogeneous, comprising at least eight complementation groups (A-H). We report that the protein encoded by the gene mutated in complementation group G (FANCG) localizes to the cytoplasm and nucleus of the cell and assembles in a molecular complex with the FANCA protein, both in vivo and in vitro. Endogenous FANCA/FANCG complex was detected in both non-FA cells and in FA cells from groups D and E. By contrast, no complex was detected in specific cell lines belonging to groups A and G, whereas reduced levels were found in cells from groups B, C, F, and H. Wild-type levels of FANCA/FANCG complex were restored upon correction of the cellular phenotype by transfection or cell fusion experiments, suggesting that this complex is of functional significance in the FA pathway. These results indicate that the cellular FA phenotype can be connected to three biochemical subtypes based on the levels of FANCA/FANCG complex. Disruption of the complex may provide an experimental strategy for chemosensitization of neoplastic cells.


Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Fanconi Anemia/genetics , Proteins/genetics , Proteins/metabolism , Cell Fusion , Cell Line , Chromosome Fragility , Fanconi Anemia Complementation Group A Protein , Fanconi Anemia Complementation Group G Protein , Genetic Complementation Test , Humans , Lymphocytes , Protein Biosynthesis , Recombinant Fusion Proteins/biosynthesis , Transfection
15.
Nat Genet ; 22(4): 379-83, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10431244

ABSTRACT

Somatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders. The best known mechanism involves intragenic mitotic recombination or gene conversion in compound heterozygous patients, whereby one allele serves to restore the wild-type sequence in the other. Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia (FA) patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC(1749T-->G, Leu496Arg) was altered by 1748C-->T, creating a cysteine codon. Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type.


Subject(s)
Cell Cycle Proteins , DNA-Binding Proteins , Fanconi Anemia/genetics , Homozygote , Mosaicism , Nuclear Proteins , Alleles , Base Sequence , Dose-Response Relationship, Drug , Fanconi Anemia Complementation Group A Protein , Fanconi Anemia Complementation Group C Protein , Fanconi Anemia Complementation Group Proteins , Female , Frameshift Mutation , Gene Deletion , Humans , Male , Methylation , Molecular Sequence Data , Phenotype , Precipitin Tests , Proteins/genetics , Transfection
16.
Am J Hum Genet ; 64(5): 1400-5, 1999 May.
Article in English | MEDLINE | ID: mdl-10205272

ABSTRACT

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disease with bone marrow failure and predisposition to cancer as major features, often accompanied by developmental anomalies. The cells of patients with FA are hypersensitive to DNA cross-linking agents in terms of cell survival and chromosomal breakage. Of the eight complementation groups (FA-A to FA-H) distinguished thus far by cell fusion studies, the genes for three-FANCA, FANCC, and FANCG-have been identified, and the FANCD gene has been localized to chromosome 3p22-26. We report here the use of homozygosity mapping and genetic linkage analysis to map a fifth distinct genetic locus for FA. DNA from three families was assigned to group FA-E by cell fusion and complementation analysis and was then used to localize the FANCE gene to chromosome 6p21-22 in an 18.2-cM region flanked by markers D6S422 and D6S1610. This study shows that data from even a small number of families can be successfully used to map a gene for a genetically heterogeneous disorder.


Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 6/genetics , Fanconi Anemia/genetics , Cell Fusion , Female , Genetic Complementation Test/methods , Genetic Markers/genetics , Humans , Male
17.
J Biol Chem ; 274(14): 9821-7, 1999 Apr 02.
Article in English | MEDLINE | ID: mdl-10092672

ABSTRACT

Activins are members of the transforming growth factor-beta family of growth and differentiation factors. In this paper, we report the results of a structure-function analysis of activin A. The primary targets for directed mutagenesis were charged, individual amino acids located in accessible domains of the protein, concentrating on those that differ from transforming growth factor-beta2, the x-ray crystal structure of which is known. Based on the activities of the recombinant activin mutants in two bioassays, 4 out of 39 mutant proteins (D27K, K102A, K102E, and K102R) produced in a vaccinia virus system were selected for further investigation. After production in insect cells and purification of these four mutants to homogeneity, they were studied in bioassays and in cross-linking experiments involving transfected receptor combinations. Mutant D27K has a 2-fold higher specific bio-activity and binding affinity to an ActRIIA/ALK-4 activin receptor complex than wild type activin, whereas mutant K102E had no detectable biological activity and did not bind to any of the activin receptors. Mutant K102R and wild type activin bound to all the activin receptor combinations tested and were equipotent in bioassays. Our results with the Lys-102 mutants indicate that the positive charge of amino acid 102 is important for biological activity and type II receptor binding of activins.


Subject(s)
Inhibins/metabolism , Protein Serine-Threonine Kinases/metabolism , Receptors, Growth Factor/metabolism , Activin Receptors, Type II , Activins , Amino Acid Sequence , Animals , Follistatin , Glycoproteins/metabolism , HeLa Cells , Humans , Inhibins/chemistry , Inhibins/genetics , Mice , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Structure, Secondary , Structure-Activity Relationship , Xenopus
18.
Nat Genet ; 20(3): 281-3, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9806548

ABSTRACT

Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms including developmental anomalies, bone marrow failure and early occurrence of malignancies. In addition to spontaneous chromosome instability, FA cells exhibit cell cycle disturbances and hypersensitivity to cross-linking agents. Eight complementation groups (A-H) have been distinguished, each group possibly representing a distinct FA gene. The genes mutated in patients of complementation groups A (FANCA; refs 4,5) and C (FANCC; ref. 6) have been identified, and FANCD has been mapped to chromosome band 3p22-26 (ref. 7). An additional FA gene has recently been mapped to chromosome 9p (ref. 8). Here we report the identification of the gene mutated in group G, FANCG, on the basis of complementation of an FA-G cell line and the presence of pathogenic mutations in four FA-G patients. We identified the gene as human XRCC9, a gene which has been shown to complement the MMC-sensitive Chinese hamster mutant UV40, and is suspected to be involved in DNA post-replication repair or cell cycle checkpoint control. The gene is localized to chromosome band 9p13 (ref. 9), corresponding with a known localization of an FA gene.


Subject(s)
DNA-Binding Proteins/genetics , Fanconi Anemia/genetics , Mutation , 5' Untranslated Regions , Animals , Base Sequence , Cell Line , Chromosome Mapping , Chromosomes, Human, Pair 9/genetics , Cricetinae , DNA, Complementary/genetics , Fanconi Anemia Complementation Group G Protein , Female , Genes, Recessive , Genetic Complementation Test , Humans , Male , Molecular Sequence Data , Pedigree , Phenotype
19.
Eur Respir J ; 10(7): 1606-13, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9230255

ABSTRACT

We studied whether neonatal chronic lung disease (NCLD), hyaline membrane disease (HMD) and differences in ventilatory support affected pulmonary function during the first year of life, in 65 infants born prematurely. The relationship between body weight and oxygen consumption (V'O2) was also analysed. The study comprised 14 infants without cardiorespiratory disease, 19 infants with HMD but without NCLD, 9 infants with NCLD without prior HMD, and 23 infants with NCLD following HMD. At 6 and 12 months corrected postnatal age, static respiratory system compliance (Crs) was measured by weighted spirometry and the functional residual capacity by closed circuit helium dilution (FRCHe) combined with assessment of ventilation distribution from the mixing index (MI). Ventilatory support during the first 5 days of therapy was quantified from peak inspiratory pressure (PIP), mean airway pressure (MAP) and fractional inspiratory concentration of oxygen (FI,O2). Infants with NCLD had a shorter duration of gestation and lower birth weight than those without NCLD (Wilcoxon, p=0.002 and p=0.001, respectively). Pulmonary function at 6 and 12 months corrected age was not different between NCLD infants with or without HMD at birth. Infants with NCLD had lower Crs and MI than those without NCLD (analysis of variance (ANOVA), p<0.011), but their FRCHe was not different. V'O2 adjusted for body weight was comparable in the four groups. PIP and FI,O2 were higher (Wilcoxon, p<0.01) in the NCLD infants than in those with HMD alone, but MAP was not different. Except for FI,O2, these indices were not different among the infants with NCLD. We conclude that birth weight is the major determinant of the development of neonatal chronic lung disease. At 6 and 12 months corrected age, the abnormal pulmonary function is not associated with prior hyaline membrane disease.


Subject(s)
Bronchopulmonary Dysplasia/diagnosis , Hyaline Membrane Disease/therapy , Birth Weight , Body Weight , Bronchopulmonary Dysplasia/epidemiology , Bronchopulmonary Dysplasia/physiopathology , Case-Control Studies , Female , Follow-Up Studies , Humans , Hyaline Membrane Disease/epidemiology , Infant , Infant, Newborn , Male , Oxygen Consumption , Respiration, Artificial , Respiratory Function Tests
20.
Endocrinology ; 138(7): 2928-36, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9202237

ABSTRACT

To gain more insight in the mechanism of action of inhibin, we studied the effect of inhibin on activin signaling in Chinese hamster ovary cells. Inhibin specifically counteracted activin-induced expression of a plasminogen activator inhibitor 1 promoter element (3TP) and of the junB gene, but was ineffective when the responses were induced by transforming growth factor-beta. This indicates that inhibin acts only on the activin-specific part of these signaling cascades. Using a constitutively active activin type IB receptor we determined whether inhibin acted at the level of the activin-receptor complex or downstream of it. The mutant activin receptor stimulated the expression of the 3TP promoter in the absence of activin. This stimulation was insensitive to inhibin, indicating that inhibin acts exclusively at or upstream of this activin type I receptor. In addition, competition studies using labeled activin showed that inhibin displaced activin from the activin type II receptors, especially from the activin type IIB receptor, but not from the type I receptors. In conclusion, these data show that in Chinese hamster ovary cells inhibin acts directly at the activin receptor complex, most likely through displacement of activin from the activin type II receptor.


Subject(s)
Gene Expression/drug effects , Inhibins/metabolism , Inhibins/pharmacology , Receptors, Growth Factor/metabolism , Signal Transduction/drug effects , Activin Receptors , Activins , Animals , CHO Cells , COS Cells , Cricetinae , Genes, Immediate-Early/drug effects , Mice , Plasminogen Activator Inhibitor 1/genetics , Promoter Regions, Genetic , Transforming Growth Factor beta/pharmacology
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