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E Bakker

Publications and source records attributed to E Bakker.

At least 73 records · Page 4Linked to original sources
PubMed1999

A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD).

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the size reduction of a polymorphic repeat array on 4q35. Probe p13E-11 recognises this chromosomal rearrangement and is generally used for diagnosis. However, diagnosis of FSHD is complicated by three factors. First, the probe cross hybridises to a highly homologous repeat array locus on chromosome 10q26. Second, although a BlnI polymorphism allows discrimination between the repeat units on chromosomes 4 and 10 and greatly facilitates FSHD diagnosis, the occurrence of translocations between chromosomes 4 and 10 further complicates accurate FSHD diagnosis. Third, the recent identification of deletions of p13E-11 in both control and FSHD populations is an additional complicating factor. Although pulsed field gel electrophoresis is very useful and sometimes necessary to detect these rearrangements, this technique is not operational in most FSHD diagnostic laboratories. Moreover, repeat arrays >200 kb are often difficult to detect and can falsely suggest a deletion of p13E-11. Therefore, we have developed an easy and reliable Southern blotting method to identify exchanges between 4 type and 10 type repeat arrays and deletions of p13E-11. This BglII-BlnI dosage test addresses all the above mentioned complicating factors and can be carried out in addition to the standard Southern blot analysis for FSHD diagnosis as performed in most laboratories. It will enhance the specificity and sensitivity of conventional FSHD diagnosis to the values obtained by PFGE based diagnosis of FSHD. Moreover, this study delimits the FSHD candidate gene region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit.

Blotting, Southern↗
PubMed1998

Somatic triple mosaicism in a carrier of X-linked chronic granulomatous disease.

The X-linked form of chronic granulomatous disease (CGD) is caused by mutations in the CYBB gene, which encodes the 91-kD subunit of the flavocytochrome b558, a component of the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytic leukocytes. Mutations in this gene are very heterogeneous and often unique for one family. Here we report on a family with two patients (brothers), one with a 3-kb deletion comprising exon 5 and the other with a 3.5-kb deletion comprising exons 6 and 7 of the CYBB gene. Sequence analysis of polymerase chain reaction (PCR)-amplified genomic DNA proved these deletions to be overlapping for 35 bp. Analysis by restriction fragment length polymorphism of genomic DNA from the mother's leukocytes showed her to be a carrier of both deletions in addition to the normal CYBB sequence. This triple somatic mosaicism was confirmed with PCR-amplified genomic and complementary DNA. The presence of the normal CYBB gene in the mother was also proven by the finding of normal superoxide-generating neutrophils in addition to cells lacking this ability. Triple X syndrome was excluded. These findings suggest that the mutations are the result of an event in early embryogenesis of the mother, possibly involving a mechanism like sister chromatid exchange.

Adolescent↗
PubMed1998

Clinical diagnosis of heterozygous dystrophin gene deletions by fluorescence in situ hybridization.

Two-thirds of patients affected by Duchenne or Becker muscular dystrophy (DMD/BMD) carry large intra-genic deletions in the dystrophin gene. In males, the deletions can be efficiently detected using multiplex polymerase chain reaction (PCR) and Southern blotting. In contrast, deletion detection in carrier females is complicated by the presence of a normal gene copy on the second X-chromosome. We have analyzed the boundaries of 570 deletions and 34 duplications in the dystrophin gene identified in the São Paulo and Leiden diagnostic laboratories. The data were used to select an optimal set of cosmid probes for the detection of the most frequently deleted areas of the dystrophin gene. Six cosmids were evaluated in fluorescence in situ hybridization (FISH) experiments to assess deletions in 21 heterozygous deletion-carriers and nine controls. No discrepancy was found between the FISH analysis and the molecular data, demonstrating the accuracy of the technique for carrier detection in Duchenne and Becker muscular dystrophy.

DNA Probes↗
PubMed1998

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.

Chromosome Mapping↗
PubMed1998

Inter- and intrachromosomal sub-telomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis.

The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD) is causally related to a short Eco RI fragment detected by probe p13E-11. This remnant fragment is the result of a deletion of an integral number of tandemly arrayed 3.3 kb repeat units (D4Z4) on 4q35. Despite intensive efforts, no transcribed sequences have been identified within this array. Previously, we have shown that these repeats on 4q35 have been exchanged for a similar highly homologous repeat locus on 10q26 in 20% of the population and that a short chromosome 10-like array on 4q35 also results in FSHD. Here, we describe the hybrid structure of some of these repeat arrays, reflecting additional sub-telomeric instability. In three healthy individuals carrying a 4-like repeat on chromosome 10 or vice versa, one repeat array was shown to consist of hybrid clusters of 4-derived and 10-derived repeat units. Moreover, employing pulsed field gel electrophoresis analysis, we identified two unrelated individuals carrying deletions of a chromosomal segment (p13E-11) proximal to the repeat locus. These deletions were not associated with FSHD. In one of these cases, however, an expansion of the deletion into the repeat array was observed in one of his children suffering from FSHD. These data provide additional evidence for instability of this sub-telomeric region and suggests that the length of the repeat, and not its intrinsic properties, is crucial to FSHD. Moreover, they are in agreement with the hypothesis that FSHD is caused by a position effect in which the repeat structure influences the expression of genes nearby. Therefore, the region deleted proximal to the repeat locus in healthy individuals can be instrumental to refine the critical region for FSHD1.

Chromosome Mapping↗
PubMed1997

The Dutch Uniform Multicenter Registration system for genetic disorders and malformation syndromes.

In medical genetics, several systems are used to classify and code genetic disorders for the purpose of automated registration. In the Netherlands, a genetic diagnosis code system has been developed that links a unique four-digit code to a principal description and all current synonyms. The main goal of this coding system is to enable nationwide uniformity of coding, without losing access to information stored in the past, identified by the ICD/BPA code (the International Classification of Diseases as adapted by the British Paediatric Association) and/or the MIM code (McKusick's classification in Mendelian Inheritance in Man). To this effect, the Dutch diagnosis code is cross-referenced with the 2 pre-existing classification systems. Developments in medical genetics make regular updates of all coding systems necessary. In the Netherlands, new diagnosis codes are assigned centrally to preserve uniformity and distributed periodically to all 8 clinical genetic centers. Diagnosis codes are assigned in numerical order of inclusion, enabling quick and easy updates. It is possible to include subclassifications of disorders according to pattern of inheritance, gene location, and gene mutations and to cover all disorders and disorder subtypes which are not clearly distinguished by the 2 pre-existing classification systems. The architecture of the coding system is suitable for international use. It offers a practical solution for clinical geneticists in need of a coding system suitable for clinical use. The use of the diagnosis code will also facilitate reliable comparison of data and nationwide genetic epidemiological studies.

Congenital Abnormalities↗
PubMed1997

Asymptomatic and late-onset ornithine transcarbamylase deficiency caused by a A208T mutation: clinical, biochemical and DNA analyses in a four-generation family.

We describe a 4-generation family in which a previously healthy 10-year-old boy died of late-onset ornithine transcarbamylase (OTC) deficiency. Pedigree analysis and allopurinol loading tests in female relatives were not informative. A missense mutation (A208T) in the OTC gene was detected in the deceased patient and in several clinically healthy male and female relatives, the oldest male being 97 years old. OTC deficiency was established in autopsy liver tissue of the propositus and liver biopsy samples of his sister, mother, and a maternal uncle. The males had 4% and 6% residual activity, respectively, the females 58% and 67%, respectively. The observed relation between the mutation and the decreased OTC activity in liver tissue of these subjects suggests that the mutation is a deleterious one. Late-onset, "mild" OTC deficiency can have a fatal or a favorable outcome. The disease can segregate undetected in families.

Adult↗
PubMed1997

Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families.

Hereditary frontotemporal dementia (HFTD) is a rare autosomal dominant form of presenile dementia characterized by behavioral changes and reduced speech. Three multigeneration kindreds with this condition, in the Netherlands, were investigated for clinicopathological comparison and linkage analysis. Frontotemporal atrophy on computed tomographic scanning and/or magnetic resonance imaging was usually present. Single-photon emission computed tomography (SPECT) showed frontal hypoperfusion in the early phase of the disease. Brain tissue showed moderate to severe atrophy of frontal and temporal cortex with neuronal loss, gliosis, and spongiosis. Pick bodies were lacking in all cases of the 3 families. The mean age of onset varied significantly between families. We report here evidence for linkage to chromosome 17q21-q22 with a maximum lod score of 4.70 at theta = 0.05 with the marker D17S932. Recombination analysis positions the gene for HFTD in a region of approximately 5 cM between markers D17S946 and D17S791. Three other neurodegenerative disorders with a strong clinical and pathological resemblance have recently been mapped to the same chromosomal region, suggesting that a group of clinically related neurodegenerative disorders may originate from mutations in the same gene.

Chromosomes, Human, Pair 17↗
PubMed1997

Dutch hereditary cerebral amyloid angiopathy: structural lesions and apolipoprotein E genotype.

Hereditary cerebral hemorrhage with amyloidosis-Dutch type is caused by a mutation at codon 693 of the beta amyloid precursor protein gene. The disease is clinically characterized by strokes and dementia. In addition to cerebral plaques, cerebral amyloid angiopathy is the pathological hallmark. We investigated the correlation between radiological (white matter hyperintensities and focal lesions on magnetic resonance images) and pathological lesions (cerebrovascular amyloid angiopathy and plaques) and the apolipoprotein E genotype in patients with the disease. Twenty-five patients were studied using magnetic resonance imaging, and brain tissue from 8 patients was studied histopathologically. Neither the white matter hyperintensity scores nor the number of focal lesions on magnetic resonance images were associated with the presence of an epsilon4 allele. Nor was a correlation found between the number and type of plaques and the apolipoprotein E genotype. All patients had severe amyloid angiopathy in all cortical areas investigated. This study showed that the apolipoprotein E genotype does not modulate amyloid-related structural lesions in hereditary cerebral hemorrhage with amyloidosis of the Dutch type.

Adult↗
PubMed1997

Presenilin-1 polymorphism and hereditary cerebral hemorrhage with amyloidosis, Dutch type.

Hereditary cerebral hemorrhage with amyloidosis, Dutch type, caused by a mutation at codon 693 of the amyloid beta precursor protein gene, is characterized by amyloid beta deposition resulting in recurrent strokes and dementia. Recent data suggest that presenilin-1 may be biologically linked to cerebral amyloid beta deposition. The intronic presenilin-1 polymorphism published by Wragg and colleagues (1996) was analyzed in 65 carriers of the hereditary cerebral hemorrhage with amyloidosis, Dutch type, mutation. We found that the presenilin-1 genotype was not correlated with age at first stroke, number of recurrences, dementia, and age at death or with white matter hyperintensities and focal lesions on magnetic resonance images. From our data we conclude that amyloid beta deposition in this disease is most likely not influenced by presenilin-1.

Adult↗
PubMed1997

Evolution of cardiac abnormalities in Becker muscular dystrophy over a 13-year period.

We evaluated the course of cardiac involvement in 27 previously reported patients with Becker muscular dystrophy (BMD) originating from nine kindreds. Since almost all affected individuals of each kindred were included, intrafamilial variability could be studied. We also attempted to identify associations between cardiac involvement, functional ability and mutations at DNA level. The mean follow-up period was 12.5 years. The number of patients with electrocardiographic abnormalities progressed from 44% to 71%. Dilated cardiomyopathy (DCM) with or without congestive heart failure was now present in 33% as compared with 15% in the previous study. In addition, 22% developed borderline echocardiographic abnormalities. Six patients (22%) became symptomatic and four patients died of congestive heart failure. In all families cardiac abnormalities were found. There was no association between DCM and mutation type. Despite equal functional motor ability, there was a considerable intrafamilial variation in cardiac involvement, even in brother pairs. We conclude that cardiac abnormalities are the rule and not the exception in BMD and are progressive over time. Left ventricular dilatation may begin at any moment in the course of BMD and the rate of progression is unpredictable. A substantial proportion of patients will develop an incapacitating and life-threatening DCM.

Adolescent↗
PubMed1997

Molecular genetic analysis of two families with keratosis follicularis spinulosa decalvans: refinement of gene localization and evidence for genetic heterogeneity.

X-linked keratosis follicularis spinulosa decalvans (KFSD) is a rare disorder affecting both skin and eyes. In the two extended KFSD families analysed to date, the gene was mapped to Xp22.13-p22.2. By analyzing several new markers in this region, we were able to narrow the candidate region to a 1-Mb interval between DXS7161 and (DXS7593, DXS7105) in the large Dutch pedigree. In addition, we analyzed 23 markers in Xp21.2-p22.2 in a German family with KFSD. Haplotype and recombination analysis positioned the KFSD gene in this family most likely outside the candidate region on Xp22.13-p22.2. This finding is suggestive for genetic heterogeneity: in this pedigree there is either another locus on the X-chromosome, or KFSD is transmitted here as an autosomal dominant trait with variable expression.

Child, Preschool↗
PubMed1997

BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients.

To date, more than 300 distinct small deletions, insertions and point mutations, mostly leading to premature termination of translation, have been reported in the breast/ovarian-cancer susceptibility gene BRCA1. The elevated frequencies of some mutations in certain ethnic subpopulations are caused by founder effects, rather than by mutation hotspots. Here we report that the currently available mutation spectrum of BRCA1 has been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PTT) and direct sequencing, using genomic DNA as template. Three large genomic deletions that are not detected by these approaches comprise 36% of all BRCA1 mutations found in Dutch breast-cancer families to date. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast-cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counselling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 4 of 170 research families, while an deletion of approximately 14 kb was detected in a single family [corrected]. Haplotype analyses indicated that each recurrent deletion had a single common ancestor.

BRCA1 Protein↗
PubMed1997

Mortality from hereditary cerebral haemorrhage with amyloidosis--Dutch type. The impact of sex, parental transmission and year of birth.

Hereditary cerebral haemorrhage with amyloidosis--Dutch type (HCHWA-D) is an autosomal dominant disorder, caused by a single base mutation in the amyloid beta precursor protein (beta PP) gene located on chromosome 21, resulting in recurrent haemorrhagic strokes and dementia. Though HCHWA-D is caused by a dominant mutation, the phenotypic expression varies widely, suggesting modulation of the phenotypic expression by additional factors. In this study we investigated the influence of sex, parental transmission and year of birth on mortality from HCHWA-D. Since the early sixties, clinical and genealogical data of patients with HCHWA-D have been collected. The standardized mortality rate (relative to the general population) was calculated to compare the mortality within the pedigrees with the mortality in the Dutch population. The influence of sex, parental transmission and year of birth on survival were studied using Cox's proportional hazard model. By December 1, 1995, a total of 187 cases were identified belonging to four large families. Mortality rate in affected individuals was fourfold increased compared with the Dutch population (relative mortality 4.0; 95% confidence interval 3.4-4.7) and higher in females than in males (relative mortality risk 8.0 and 2.6, respectively). Mortality rate was lower when HCHWA-D was maternally transmitted (mortality relative to paternal transmission 0.7; 95% confidence interval 0.5-1.0). Year of birth had no effect on the mortality of the affected individuals. Survival of HCHWA-D has not yet increased, in spite of higher standards of general medicine, i.e. the mortality rate did not decline over the years. Female sex was a major factor increasing mortality rate in HCHWA-D. Paternal transmission had a just significant effect on mortality rate in HCHWA-D. The possible mechanisms behind these phenomena remain unexplained by this clinical study.

Amyloid beta-Protein Precursor↗
PubMed1997

Estimating Y chromosome specific microsatellite mutation frequencies using deep rooting pedigrees.

Recently, a set of highly polymorphic chromosome Y specific microsatellites became available for forensic, population genetic and evolutionary studies. However, the lack of a mutation frequency estimate for these loci prevents a reliable application. We therefore used seven chromosome Y tetranucleotide repeat loci to screen 42 males who are descendants from 12 'founding fathers' by a total number of 213 generations. As a result, we were able to estimate an average chromosome Y tetranucleotide mutation frequency of 0.20% (95% CIL 0.05-0.55). This closely matches the often cited Weber and Wong estimate of 0.21% for a set of autosomal tetranucleotide repeats. Expanding the set of microsatellites with two more loci (a tri- and a penta-nucleotide repeat locus) an average chromosome Y microsatellite mutation frequency of 0.21% (95% CIL 0.06-0.49) was found. These estimates suggest that microsatellites on the Y chromosome have mutation frequencies comparable to those on the autosomes. This supports the hypothesis that slippage-generated growth is the driving force behind the microsatellite variability.

Gene Frequency↗
PubMed1997

The clinical and molecular genetic approach to Duchenne and Becker muscular dystrophy: an updated protocol.

Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystrophy is possible in about 65-70% of patients by Southern blotting or multiplex PCR. Subsequently, carrier detection is possible by assessing the intensity of relevant bands, but preferably by a non-quantitative test method. Detection of microlesions in Duchenne and Becker muscular dystrophy is currently under way. Single strand conformational analysis, heteroduplex analysis, and the protein truncation test are mostly used for this purpose. In this paper we review the available methods for detection of large and small mutations in patients and in carriers and propose a systematic approach for genetic analysis and genetic counselling of DMD and BMD families, including prenatal and preimplantation diagnosis.

DNA Mutational Analysis↗
PubMed1997

Prenatal diagnosis of the fragile X syndrome: loss of mutation owing to a double recombinant or gene conversion event at the FMR1 locus.

The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMR1 gene. In patients with an expanded repeat the FMR1 promoter is methylated and, consequently, the gene is silenced and no FMR1 protein (FMRP) is produced, thus leading to the clinical phenotype. Here we describe a prenatal diagnosis performed in a female from a fragile X family carrying a large premutation. In chorionic villus DNA of the male fetus the normal maternal CGG allele and a normal pattern on Southern blot analysis were found in combination with the FRAXAC2 and DXS297 allele of the maternal at risk haplotype. A second chorionic villus sampling was performed giving identical results on DNA analysis and, in addition, expression of FMRP was shown by immunohistochemistry. We concluded that the male fetus was not affected with the fragile X syndrome. Subsequent detailed haplotype analysis showed a complex recombination pattern resembling either gene conversion or a double crossover within a 20 kb genomic region.

Alleles↗