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E Bakker

Publications and source records attributed to E Bakker.

At least 91 records · Page 5Linked to original sources
PubMed1997

Pitt-Rogers-Danks syndrome and Wolf-Hirschhorn syndrome are caused by a deletion in the same region on chromosome 4p 16.3.

Recently, a deletion of chromosome 4pter was found in three patients with Pitt-Rogers-Danks syndrome. We investigated two of these patients, by means of DNA and FISH studies, together with two additional patients with Pitt-Rogers-Danks syndrome, to determine the critical region of the deletion in these patients and to compare this with the critical region in Wolf-Hirschhorn syndrome. All four patients showed terminal deletions of chromosome 4p of different sizes. One of them appeared to have an unbalanced karyotype caused by a cryptic translocation t(4;8) in the mother, resulting in a deletion of chromosome 4pter and a duplication of chromosome 8pter. The localisation of the Wolf-Hirschhorn critical region has been confined to approximately 1 Mb between D4S43 and D4S115. Our study shows that the deletions in four patients with the Pitt-Rogers-Danks syndrome overlap the Wolf-Hirschhorn critical region and extend beyond this in both directions. This study, combined with the fact that our third patient, who was previously described as a Pitt-Rogers-Danks patient, but who now more closely resembles a Wolf-Hirschhorn patient, makes it likely that Pitt-Rogers-Danks and Wolf-Hirschhorn syndromes are different clinical phenotypes resulting from a deletion in the same microscopic region on chromosome 4p16.

Abnormalities, Multiple↗
PubMed1997

Location on the human genetic linkage map of 26 genes involved in blood coagulation.

Several human genetic linkage maps have been constructed as part of the Human Genome Project. These maps show the positional order of closely linked, highly informative AC-repeat polymorphisms on each human chromosome, and are extremely useful in genetic linkage analysis of inheritable diseases. For a candidate gene approach the current linkage maps are less useful, since they consist mainly of anonymous markers rather than of specific genes. This situation also applies for inheritable disorders of blood coagulation. Numerous genes are involved in the blood coagulation cascade and its regulation, and can be considered as candidate genes for unexplained haemophilia and thrombophilia. We have selected 29 candidate genes that seem to be the ones most likely to be involved in thrombophilia. For 19 genes genotype data were already present in the CEPH database (version 7.0). We typed 7 additional genes in the CEPH reference families, i.e. the factor V, factor XII, protein C, protein S, prothrombin, thrombomodulin, and heparin cofactor II gene. The genotype data were used to integrate these 26 genes in the current genetic linkage map, and to identify closely linked AC-repeat polymorphisms. This information will benefit the investigation of inheritable disorders of blood coagulation, especially thrombophilia.

Base Sequence↗
PubMed1996

Miniature sodium-selective ion-exchange optode with fluorescent pH chromoionophores and tunable dynamic range.

An extension into the fluorescence mode of ion-exchange optodes is described, allowing miniaturization and its concomitant benefits. A micrometer-size, fluorescent fiber-optic sodium sensor is described, based on a highly sodium-selective, crown ether-capped calix[4]arene ionophore, capable of ratiometric operation. Three sensor configurations are given, employing different lipophilic, fluorescent pH chromoionophores (Nile Blue derivatives), demonstrating the ability to improve the detection limit and tune the dynamic range to the desired region of interest. Two of the sensors are of special interest in that their working ranges lie within those desired for measuring intracellular cytosolic or blood levels of sodium at the respective physiological pH. These optodes have excellent sodium selectivity, with other physiologically relevant cations (e.g., potassium, calcium, and magnesium) being highly discriminated. Three simple mathematical relationships are given for the three experimentally used fluorescent signal mechanisms (intensity, intensity ratios, and inner-filter or energy transfer effects), permitting visualization on a single graph and enabling direct comparison of the different sensors' optical responses on a common platform. Finally, these optodes measure the sample's sodium activity, rather than the concentration, provided that the sample's pH is measured simultaneously by another sensor, such as a glass electrode.

Fiber Optic Technology↗
PubMed1996

Influence of nonionic surfactants on the potentiometric response of hydrogen ion-selective polymeric membrane electrodes.

The influence of poly(ethylene oxide)-based nonionic surfactants (i.e., Triton X-100 and Brij 35) in the sample phase on the response properties of hydrogen ion-selective polymeric membrane electrodes containing mobile (lipophilic amines) or covalently bound (aminated-poly-(vinyl chloride)) hydrogen ion carriers is reported. In the presence of these nonionic surfactants, membrane electrode response toward interfering cation activity (e.g., Na+) in the sample phase is increased substantially and the pH measuring range shortened. The degree of cation interference for pH measurements is shown to correlate with the basicity of the hydrogen ion carrier doped within the membrane phase. The observed deterioration in selectivity arises from the partitioning of the surfactant into the membrane and concomitant extraction of metal cations by the surfactants in the organic phase. The effect of nonionic surfactants on pH electrodes prepared with aminated-PVC membranes is shown to be more complex, with additional large shifts in EMF values apparently arising from multidentate interactions between the surfactant molecules and the polymeric amine in the membrane, leading to a change in the apparent pKa values for the amine sites. The effects induced by nonionic surfactants on the EMF response function of hydrogen ion-selective polymeric membrane electrodes are modeled, and experimental results are shown to correlate well with theoretical predictions.

Electrodes↗
PubMed1996

Application of in vitro Myo-differentiation of non-muscle cells to enhance gene expression and facilitate analysis of muscle proteins.

Introduction of the myogenic-determination gene MyoD forces non-muscle cell cultures into myogenesis, thereby inducing expression of muscle-specific proteins and facilitating their analysis. In several MyoD-transfected fibroblasts, immunohistochemical detection showed expression of desmin after three days, of titin after five days and of dystrophin after seven days. Cell fusion (myotube formation) could be observed after five days. After nine days a fraction of the cells showed a striated titin pattern, indicating an advanced state of muscle differentiation. Dystrophin (the protein absent in Duchenne Muscular Dystrophy patients) can be detected in MyoD-transfected and differentiated fibroblasts from healthy individuals, and is absent in those of patients. MyoD-transfection increases transcription of the dystrophin gene, facilitating RNA-based mutation detection. Using RNA from MyoD-transfected, differentiated fibroblasts of a deceased patient with an unknown, non-deletion mutation, we were able to identify a CGA-->TGA nonsense mutation in the rod domain at basepair 6492 and to establish a rapid mutation specific test for future diagnosis of the mutation in his relatives.

Base Composition↗
PubMed1996

The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands.

A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10(-6). The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.

Adolescent↗
PubMed1996

Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy, clinically characterized by asymmetric weakness of muscles in the face, shoulder girdle and upper arm. Deletion of an integral number of 3.3 kb repeated units within a highly polymorphic EcoRI fragment at chromosome 4q35, generating a relatively short EcoRI fragment (< 35 kb), has been shown to cause FSHD1. Probe p13E-11 detects these short fragments in FSHD1 patients, and has therefore been used for diagnostic DNA analysis. However, the reliability of this analysis has been hampered by cross-hybridization of p13E-11 to chromosome 10q26-linked EcoRI fragments of comparable size, which also contain a variable number of 3.3 kb repeated units. Recently, a BinI restriction site was identified within each of the repeated units derived from chromosome 10q26, which enables differentiation of the two polymorphic p13E-11 loci in most cases without haplotype analysis. Remarkably, applying the differential analysis to screen DNA of 160 Dutch cases referred to us for FSHD1 diagnosis, we obtained evidence for subtelomeric exchange of 3.3 kb repeated units between chromosomes 4q35 and 10q26 in affected and unaffected individuals. Subsequently, analysis of 50 unrelated control samples indicated such exchange between chromosomes 4q35 and 10q26 in at least 20% of the population. These subtelomeric rearrangements have generated a novel interchromosomal polymorphism, which has implications for the specificity and sensitivity of the differential restriction analysis for diagnostic purposes. Moreover, the high frequency of the interchromosomal exchanges of 3.3 kb repeated units suggests that they probably do not contain (part of) the FSHD1 gene, and supports position effect variegation as the most likely mechanism for FSHD1.

Chromosomes, Human, Pair 10↗
PubMed1996

Analysis of molecular variance (AMOVA) of Y-chromosome-specific microsatellites in two closely related human populations.

The analysis of seven Y-chromosome-specific microsatellite loci revealed a high level of polymorphism in two closely related human populations (Dutch, n = 89, and German, n = 70). Four of these loci were found to generate at least 77 different haplotypes, only 15 of which were shared by the two populations. These results demonstrate that highly informative PCR-based DNA typing of the Y chromosome is now feasible. Assuming a stepwise mutation model, a network comprising all minimum spanning evolutionary trees connecting the haplotypes was constructed. Analysis of molecular variance based upon this network indicated that the within-population heterogeneity with respect to haplotype descent was significantly smaller than the between-population heterogeneity, suggesting that males were more closely related to males from their own population as opposed to males from the other population. These findings suggest that Y-chromosomal microsatellites might be very useful not only for forensic purposes but also in association studies of multifactorial traits, allowing the characterization of the level of genetic distinctiveness of supposedly inbred or isolated populations and discrimination even between closely related populations.

Analysis of Variance↗
PubMed1996

Asymptomatic and late-onset ornithine transcarbamylase (OTC) deficiency in males of a five-generation family, caused by an A208T mutation.

In a large five-generation Polish family, late-onset ornithine transcarbamylase (OTC) deficiency in males segregated with the missense mutation Ala208Thr (A208T), and all heterozygous females were asymptomatic. No other mutations were found in the coding sequences and intron-exon boundaries of the OTC gene. Surprisingly, the mutation originated from the great-grandfather of the index patient who died at age 59 of liver carcinoma. He never had dietary restrictions or hyperammonemic spells throughout life and appears to be the oldest male reported with OTC deficiency. The index patient had a severe OTC deficiency (3% of normal). Eight males died suddenly at ages 4 months to 23 years (average 14 years) after a foudroyant episode triggered by a common infection. The patients remained undiagnosed for 28 years because a metabolic defect was not considered to be the cause of the acute episodes. Recognition of the familial pattern of inheritance was initially unnoticed since the patients were admitted to eight different hospitals. DNA analysis predicted that two 'healthy' boys also had OTC deficiency, which was confirmed by abnormal results of allopurinol challenge tests. Initial suspicion of OTC deficiency in such families is complicated, since symptoms can develop at any age, or even remain absent. This obscures the typical pattern of X-linked inheritance in small families.

Age of Onset↗
PubMed1996

European Gene Mapping Project (EUROGEM): breakpoint panels for human chromosomes based on the CEPH reference families. Centre d'Etude du Polymorphisme Humain.

Meiotic breakpoint panels for human chromosomes 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 17, 18, 20 and X were constructed from genotypes from the CEPH reference families. Each recombinant chromosome included has a breakpoint well-supported with reference to defined quantitative criteria. The panels were constructed at both a low-resolution, useful for a first-pass localization, and high-resolution, for a more precise placement. The availability of such panels will reduce the number of genotyping experiments necessary to order new polymorphisms with respect to existing genetic markers. This paper shows only a representative sample of the breakpoints detected. The complete data are available on the World Wide Web (URL http:/(/)www.icnet.uk/axp/hgr/eurogem++ +/HTML/data.html) or by anonymous ftp (ftp.gene.ucl.ac.uk in/pub/eurogem/maps/breakpoints).

Chromosome Mapping↗
PubMed1996

Diagnostic, predictive, and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the common inherited neuromuscular disorders. The major gene involved, FSHD1, has been localised to chromosome 4q35. This 4q35 locus, detected by pE13-11 (D4F104S1), shows a mutation frequency of about 10% of the incidence. New mutants are characterised by de novo deletions of tens to hundreds of kilobases of DNA. Although these deletion fragments are very useful as a molecular genetic tool, their use in diagnostic DNA testing is hampered by multiple factors, particularly in familial cases. In this report we describe a protocol that can be used for DNA testing in well defined familial cases or proven de novo cases, and in the differential diagnosis of muscular dystrophy patients clinically suspected of having FSHD. In addition, we describe a prenatal diagnosis performed for FSHD1.

DNA↗
PubMed1996

Splicing mutations in DMD/BMD detected by RT-PCR/PTT: detection of a 19AA insertion in the cysteine rich domain of dystrophin compatible with BMD.

We have used an RNA based mutation detection method to screen the total coding region of the dystrophin gene of a Duchenne and a Becker muscular dystrophy patient in whom DNA based mutation detection methods have so far failed to detect mutations. By RT-PCR and the protein truncation test (PTT) we could identify point mutations in both cases. DMD patient DL184.3 has a T-->A mutation in intron 59 at position -9, creating a novel splice acceptor site for exon 60. As a result seven intronic bases are spliced into the mRNA, causing a frameshift and premature translation termination 20 codons downstream. Since this patient had died and only fibroblasts were available, we applied MyoD induced myodifferentiation of stored fibroblasts to enhance muscle specific gene expression. With the results of this mutation analysis, prenatal diagnosis could subsequently be performed in this family. BMD patient BL207.1 carries a G-->C mutation at position +5 of intron 64, disrupting the splice donor consensus sequence and activating a cryptic splice donor site 57bp downstream. The inclusion of these 57 intronic bases in the mRNA leaves the reading frame open and results in the insertion of 19 amino acids into the cysteine rich domain of dystrophin. Interestingly, this insertion in a part of the dystrophin considered to interact with the dystrophin binding complex of the sarcolemma is apparently compatible with mild BMD-like clinical features. Both mutations reported are missed by analysis of multiplex PCR products designed for deletion screening of the coding region. Extrapolation from existing point mutation detection efficiencies by DNA and RNA based methods emphasises that RNA based methods are more sensitive and that most of the remaining undetected mutations may affect splice or branch sites or create cryptic splice sites.

Adolescent↗
PubMed1996

Main clinical features of the three mapped autosomal recessive limb-girdle muscular dystrophies and estimated proportion of each form in 13 Brazilian families.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a group of muscle diseases with a wide spectrum of clinical signs, varying from very severe to mild. Four different loci that when mutated cause the AR LGMD phenotype have been mapped or cloned or both: in two of them the linked families seem to have a relatively mild phenotype (LGMD2a and LGMD2b), in the third one the reported linked families show a more severe clinical course (LGMD2c), while mutations in the fourth locus may cause severe or mild phenotypes (LGMD2d). The relative proportion of each of these genetic forms among the LGMD families and whether there are other genes that when mutated cause this phenotype is unknown. The closest available informative markers for each of the mapped AR LGMD genes have been tested in 13 Brazilian families with at least three affected patients. The findings from the present report confirm non-allelic heterogeneity for LGMD and suggest that in our population about 33% of the LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% may be by mutations at the 13q locus. They also suggest that there is at least one other gene responsible for this phenotype. In addition, the main clinical features of the different forms are discussed.

Adolescent↗
PubMed1996

First experiences with genetic counselling based on predictive DNA diagnosis in hereditary glomus tumours (paragangliomas).

Hereditary glomus tumour (MIM 168,000) or paraganglioma (PGL) is a slowly progressive disorder causing benign tumour growth predominantly in the head and neck region. Though benign in nature the tumours can lead to severe morbidity. Inheritance of PGL is autosomal dominant and is strongly modified by genomic imprinting; only a paternally transmitted PGL gene leads to symptoms. A gene for PGL has recently been mapped to 11q22.3-q23. Genetic counselling on the basis of DNA linkage diagnosis was offered in an extended Dutch pedigree. Thirty-two subjects opted for further counselling, of whom 20 applied for DNA testing and participated in a standardised protocol. Sixteen cases had presymptomatic testing (paternal allele); four of these appeared to have the at risk haplotype and in two of them a glomus tumour was subsequently detected on MRI. In one case linkage results were inconclusive (recombination) and one person did not want to learn his test result. Four cases had testing for carrier status (maternal allele) of which one appeared to be a carrier. Our data show that genetic counselling gains significant accuracy when based on parent of origin, sex of the counsellee, and DNA linkage diagnosis. Moreover, a normal DNA result may prevent unnecessary worry and investigations, while an established presymptomatic diagnosis will guide adequate clinical management. The psychological impact of counselling and predictive DNA testing is unclear as yet. Further investigations into the natural history of PGL in gene carriers and into the psychological impact of DNA testing is desirable.

DNA, Neoplasm↗
PubMed1995

Confirmation of the 2p locus for the mild autosomal recessive limb-girdle muscular dystrophy gene (LGMD2B) in three families allows refinement of the candidate region.

The mild autosomal recessive limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of muscle diseases. The first gene to be mapped and associated with this phenotype was a locus on 15q based on linkage analysis in families from a French geographic isolate. These results have been confirmed in other populations, but it was shown that there is genetic heterogeneity for this form of LGMD. Recently, a second locus has been mapped to chromosome 2p. The confirmation of the mapping of this second locus in LGMD families from different populations is of utmost importance for the positional cloning of this gene (HGMW-approved symbol LGMD2B). In this publication, haplotypes generated from five chromosome 2 markers from all of the known large families linked to chromosome 2p are reported together with the recombinants that show the current most likely location of the LGMD 2B gene.

Chromosome Mapping↗
PubMed1995

Denaturing and non-denaturing gel electrophoresis as methods for the detection of junctional diversity in rearranged T cell receptor sequences.

Two nucleic acid gel electrophoresis techniques were tested as a possible tool for analyzing junctional diversity in rearranged T cell receptor (TcR) sequences in order to define the extent of T cell heterogeneity. For this purpose denaturing gradient gel electrophoresis (DGGE) as well as non-denaturing gel electrophoresis (nDGE) techniques have been studied. Detection of junctional diversity is based on mobility shifts, caused by nucleotide sequence polymorphism, of polymerase chain reaction amplified rearranged TcR sequences. DGGE as well as nDGE procedures are suitable for the detection of junctional diversity in TcR V gene family sequences based on sequence dependent separation. Compared to DGGE, nDGE of DNA is a relatively simple and rapid procedure, with a high separation potential. nDGE permits separation of double stranded (homoduplexes) and/or single stranded DNA molecules of the majority of TcR chain encoding sequences. Formation and detection of unique heteroduplex molecules combined with single stranded DNA molecule analysis in nDGE permits the recognition of the remaining sequences, thus providing additional information on the degree of T cell heterogeneity. In conclusion, these nucleic acid gel electrophoresis techniques allow a direct assessment of the heterogeneity and clonality of T cell populations by the detection of junctional diversity in TcR chain encoding sequences. This analysis can be performed without the need of cell propagation and/or cellular cloning procedures, thereby eliminating the risk of introducing technical artefacts.

Animals↗
PubMed1995

Prenatal diagnosis of the urea cycle diseases: a survey of the European cases.

A European survey of prenatal diagnosis cases involving urea cycle diseases was performed. Citrullinemia was the most frequently investigated disease (108 cases). Other diseases are, in order of frequency, argininosuccinic aciduria (75 cases), ornithine transcarbamylase defect (52 cases), carbamoylphosphate synthetase defect (8 cases), triple H (3 cases), and arginase deficiency (1 case). Only one disease (ornithine transcarbamylase defect) is presently diagnosed using molecular biology methods.

Argininosuccinic Acid↗