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C Wijmenga

Publications and source records attributed to C Wijmenga.

At least 55 records · Page 3Linked to original sources
PubMed1999

Isochromosome 1q as the sole chromosomal abnormality in two fetal teratomas. Possible trisomic or tetrasomic zygote rescue in fetal teratoma with an additional isochromosome 1q.

An isochromosome of the long arm of chromosome 1 leading to tetrasomy 1q was detected as the sole chromosomal aberration in two cases of fetal teratoma arising from the oral cavity. This type of teratoma is extremely rare and has seldom been investigated cytogenetically. Studies of DNA markers in the tumor, normal fetal skin, and parental cells demonstrated that in both cases the additional 1q material was of maternal origin. In one of the patients, the teratoma had maternal 1q marker alleles that were not found in the fetal body cells. This implies that the tumor was not derived in a direct way from the fetal body tissue; instead, the chromosomally-normal fetus might be the result of some trisomic or tetrasomic zygote rescue mechanism.

Alleles↗
PubMed1999

Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16.

Abnormal hepatic copper accumulation is recognized as an inherited disorder in man, mouse, rat and dog. The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene, causing Wilson disease (WD). Mutations in the ATP7B genes have also been demonstrated in mouse and rat. The ATP7B gene has been excluded in the much rarer human copper overload disease non-Indian childhood cirrhosis, indicating genetic heterogeneity. By investigating the common autosomal recessive copper toxicosis (CT) in Bedlington terriers, we have identified a new locus involved in progressive liver disease. We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co-localization of ATP7B and C04107, using fluorescence in situ hybridization (FISH). C04107 is an anonymous microsatellite marker closely linked to CT. However, BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respectively, demonstrating that WD cannot be homologous to CT. The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22. 2-22.5. A transcribed sequence identified from the C04107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p13-p16, a region devoid of any positional candidate genes.

Adenosine Triphosphatases↗
PubMed1998

Polymorphic detection of a parthenogenetic maternal and double paternal contribution to a 46,XX/46,XY hermaphrodite.

True hermaphroditism in humans usually is associated with a 46,XX karyotype or with mosaicism in which admixtures of cells with an XX and an XY karyotype are seen. However, the mechanisms that cause such mosaicisms are poorly understood. To date, with rare exceptions, analyses of hermaphrodites have been limited mostly to cytogenetic investigations. In this report, we describe a 5-year-old patient with true hermaphroditism and a 46,XX/46,XY karyotype (ratio 38:12) in lymphocytes, suggesting involvement of two fertilization events. Microsatellite DNA polymorphisms distributed throughout the genome were analyzed, to investigate the origin of the cell lines concerned. The results are consistent with double paternal and single maternal genetic contributions. Possible mechanisms that would explain these findings are discussed. The most likely mechanism involves a single haploid ovum dividing parthenogenetically into two haploid ova, followed by double fertilization and fusion of the two zygotes into a single individual, at the early embryonic stage.

Child, Preschool↗
PubMed1998

Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.

Immunodeficiency in association with centromere instability of chromosomes 1, 9, and 16 and facial anomalies (ICF syndrome) is a rare autosomal recessive disorder. ICF patients show marked hypomethylation of their DNA; undermethylation of classical satellites II and III is thought to be associated with the centromere instability. We used DNA from three consanguineous families with a total of four ICF patients and performed a total genome screen, to localize the ICF syndrome gene by homozygosity mapping. One chromosomal region (20q11-q13) was consistently found to be homozygous in ICF patients, whereas all healthy sibs showed a heterozygous pattern. Comparison of the regions of homozygosity in the four ICF patients localized the ICF locus to a 9-cM region between the markers D20S477 and D20S850. Analysis of more families will be required, to refine the map location further. Isolation of the gene associated with the ICF syndrome not only will give insight into the etiology of the ICF syndrome but will also broaden our understanding of DNA methylation processes.

Chromosome Mapping↗
PubMed1996

Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11.

The fusion oncogene CBFB-MYH11 is generated by a chromosome 16 inversion in human acute myeloid leukemia subtype M4Eo. Mouse embryonic stem (ES) cells heterozygous for this oncogene were generated by inserting part of the human MYH11 cDNA into the mouse Cbfb gene through homologous recombination (knock-in). Chimeric mice were leukemia free, but the ES cells with the knocked-in Cbfb-MYH11 gene did not contribute to their hematopoietic tissues. Mouse embryos heterozygous for Cbfb-MYH11 lacked definitive hematopoiesis and developed multiple fatal hemorrhages around embryonic day 12.5. This phenotype is very similar to that resulting from homozygous deletions of either Cbfb or Cbfa2 (AML1), consistent with a dominant negative function of the Cbfb-MYH11 fusion oncogene. An impairment of primitive hematopoiesis was also observed, however, suggesting a possible additional function of Cbfb-MYH11.

Amino Acid Sequence↗
PubMed1996

Core binding factor beta-smooth muscle myosin heavy chain chimeric protein involved in acute myeloid leukemia forms unusual nuclear rod-like structures in transformed NIH 3T3 cells.

Patients with the M4Eo subtype of acute myeloid leukemia almost invariably are found to have an inversion of chromosome 16 in their leukemic cells, which results in a gene fusion between the transcription factor called core binding factor beta (CBFbeta) on 16q and a smooth muscle myosin heavy chain (SMMHC) gene on 16p. Subcellular localizations of the wild-type CBFbeta and the CBFbeta-SMMHC fusion protein were determined by immunofluorescence of NIH 3T3 cells that overexpress wild-type or fusion protein. Normal CBFbeta showed an unexpected perinuclear pattern consistent with primary localization in the Golgi complex. The CBFbeta-SMMHC fusion protein had a very different pattern. Nuclear staining included rod-like crystalline structures as long as 11 microm. The heterodimeric partner of CBFbeta, CBFalpha, formed part of this complex. Cytoplasmic staining included stress fibers that colocalized with actin, probably as a consequence of the myosin heavy chain component of the fusion protein. Deletion of different regions of the CBFbeta portion of the fusion protein showed that binding to CBFalpha was not required for nuclear translocation. However, deletion of parts of the SMMHC domain of the fusion protein involved in myosin-mediated filament formation resulted in proteins that did not form rod-like structures. These observations confirm previous indirect evidence that the CBFbeta-SMMHC fusion protein is capable of forming macromolecular nuclear aggregates and suggests possible models for the mechanism of leukemic transformation.

3T3 Cells↗
PubMed1996

Identification of the chimeric protein product of the CBFB-MYH11 fusion gene in inv(16) leukemia cells.

An expressed gene formed by fusion between the CBFB transcription factor gene and the smooth muscle myosin heavy chain gene MYH11 is consistently detected by reverse transcription polymerase chain reaction (RT-PCR) in patients who have acute myeloid leukemia (AML) subtype M4Eo with an inversion of chromosome 16. We have previously shown that a CBFB-MYH11 cDNA construct can produce a chimeric protein and transform NIH 3T3 cells. However, the presence of the chimeric protein in patient cells has not been demonstrated previously. Here, we show that such chimeric proteins can be identified in vivo, primarily in the nuclei of the leukemic cells, by use of antibodies against the C-terminus of the smooth muscle myosin heavy chain and the fusion junction peptide. A very high molecular weight protein/DNA complex is generated when nuclear extracts from patient cells are used in electrophoretic mobility shift assays, as seen in NIH 3T3 cells transfected with the CBFB-MYH11 cDNA. Immunofluorescence staining shows that the proteins are organized in vivo into novel structures within cell nuclei. One isoform of the transcript of the CBFB-MYH11 fusion gene, containing the MHC204 C-terminus, was the predominant from in all five cases studied.

3T3 Cells↗
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↗
PubMed1995

Identification of a new murine runt domain-containing gene, Cbfa3, and localization of the human homolog, CBFA3, to chromosome 1p35-pter.

Core binding factor (CBF) is a heterodimeric transcription factor composed of two distinct subunits. The monomeric beta subunit is ubiquitously expressed, whereas expression of the three alpha subunits isolated previously seems to be restricted mainly to hematopoietic tissues. To isolate additional alpha genes, degenerate oligonucleotides derived from the runt domain--a region shared by all alpha genes--were used for screening cDNA libraries. A 228-bp fragment was isolated from a mouse thymus cDNA library, which showed 82 and 76% DNA sequence identity to the previously isolated murine alpha genes, Cbfa1 and Cbfa2. This novel alpha gene was named Cbfa3. The corresponding sequence from the human homolog CBFA3 was obtained by cosmid cloning and sequencing of the appropriate restriction fragment. The corresponding regions of mouse Cbfa3 and human CBFA3 show 91% nucleotide identity and 100% protein identity. In situ hybridization and physical mapping of somatic cell hybrids localized CBFA3 to chromosome 1p35-pter.

Amino Acid Sequence↗
PubMed1995

Genetic mapping of the dentinogenesis imperfecta type II locus.

Dentinogenesis imperfecta type II (DGI-II) is an autosomal dominant disorder of dentin formation, which has previously been mapped to chromosome 4q12-21. In the current study, six novel short tandem-repeat polymorphisms (STRPs) have been isolated, five of which show significant evidence of linkage to DGI-II. To determine the order of the STRPs and define the genetic distance between them, nine loci (including polymorphisms for two known genes) were mapped through the CEPH reference pedigrees. The resulting genetic map encompasses 16.3 cM on the sex-averaged map. To combine this map with a physical map of the region, all of the STRPs were mapped through a somatic cell hybrid panel. The most likely location for the DGI-II locus within the fixed marker map is in the D4S2691-D4S2692 interval of 6.6 cM. The presence of a marker that shows no recombination with the DGI-II phenotype between the flanking markers provides an important anchor point for the creation of physical continuity across the DGI-II candidate region.

Base Sequence↗
PubMed1995

Fish mapping of 250 cosmid and 26 YAC clones to chromosome 4 with special emphasis on the FSHD region at 4q35.

Facioscapulohumeral muscular dystrophy (FSHD) is located on chromosome 4q35, close to the telomere. FSHD patients carry deletions within a cluster of tandemly repeated DNA. Although expression of a functional FSHD gene will be altered in patients, the sequence itself may be unaffected by this deletion. Hence, the FSHD gene could lie outside of the deleted region. This study employs fluorescent in situ hybridization using chromosome 4-specific cosmid and YAC clones to rapidly saturate chromosome 4 with new markers. Some 250 cosmids and 26 YACs were regionally mapped, of which 5 YACs and 55 cosmids mapped to the distal portion of 4q. Only one of these clones (D4S1454) mapped telomerically to a translocation breakpoint specified by D4S187. Using two-color interphase mapping, the following marker order was obtained: Cen-D4S187-D4S1454-HSPCAL2-D4S163-D4S139-+ ++D4F35S1. Absence of additional markers mapping distal to D4F35S1 indicates that the linkage group containing the FSHD gene lies extremely close to the 4q telomere.

Cell Line↗
PubMed1995

Search for the FSHD gene using cDNA selection in a region spanning 100 kb on chromosome 4q35.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by deletions of 3.3-kb tandemly repeated units contained within a large polymorphic EcoRI fragment close to the telomere of chromosome 4q. Since the rearrangements were assumed to interfere with the structure or function of the putative FSHD gene, the gene search was focused on cosmids containing these repeat units and, in addition, cosmids spanning 75 kb of upstream sequences. cDNA selection hybridization was applied to four overlapping cosmid clones, yielding a total of 150 putative cDNA clones. These clones showed a random distribution across the cosmid contig, except for three regions which contained a much larger number of clones. Nine cDNA clones hybridized to a 2.2-kb EcoRI fragment, located 22 kb centromeric to the 3.3-kb repeated units. This 2.2-kb fragment showed evolutionary conservation, and analysis of the sequence by "GRAIL" predicted the presence of several exons. Transcripts homologous to this fragment could be identified but none of them originated from the 4q35 locus. Strikingly, most clones revealed 4-10 homologous loci, and no single copy clones could be isolated. These findings are in line with earlier observations by fluorescent in situ hybridization (FISH) showing hybridization of individual cosmid clones to multiple chromosomes. The presence of homologous regions on other chromosomes seriously complicates the cloning of the FSHD gene.

Blotting, Northern↗
PubMed1995

The FSHD-linked locus D4F104S1 (p13E-11) on 4q35 has a homologue on 10qter.

Facioscapulohumeral muscular dystrophy (FSHD) has recently been shown to be associated with deletions that are detectable using probe p13E-11 (D4F104S1). Although these deletions reside within large, highly polymorphic restriction fragments (20-300 kb), the "mutant" fragment is usually shorter than 28 kb and can routinely be detected using conventional agarose gel electrophoresis. Yet, the complete visualization of the alleles requires pulsed-field gel electrophoresis (PFGE). Family studies showed that p13E-11 detects two nonallelic loci in this size range, only one of which originates from chromosome 4q35. We have assigned the other p13E-11 locus to chromosome 10qter by linkage analysis in CEPH pedigrees. Knowing the location of both loci improves the diagnostic reliability, as the exact origin of "small" EcoRI fragments can be determined by haplotyping. Since FSHD shows genetic heterogeneity, this 10qter locus became an interesting candidate to be the second FSHD locus. However, analysis of a large chromosome 4-unlinked FSHD family did not provide evidence for linkage on chromosome 10qter.

Chromosome Mapping↗
PubMed1995

Early onset facioscapulohumeral muscular dystrophy.

We report 10 patients (5 familial, 5 sporadic) with facioscapulohumeral muscular dystrophy (FSHD) with onset of facial and shoulder girdle weakness in early infancy. They showed the same broad range of clinical signs and symptoms as can be seen normally in FSHD. In 7 patients Southern blotting with p13E-11 was performed which showed an abnormal EcoRI fragment (13-22 kb) in 6 of them. We conclude that early onset FSHD does not differ from regular FSHD clinically or genetically. However, the precise mechanisms involved in the extensive clinical variability of the disease are still unknown.

Adolescent↗
PubMed1995

On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy.

We have performed retinal fluorescein angiography and audiometry in 32 familial and 7 sporadic cases of facioscapulohumeral muscular dystrophy. A mild to moderate retinal vasculopathy, consisting of retinal teleangiectasis and microaneurysms, was present in 18 of 37 evaluable angiograms (49%); 5 patients had minimal changes and 14 angiograms (38%) were normal. High frequency hearing loss was found in 25 (64%) out of 39 patients. Retinal changes were absent in 5 of 18 families (6 cases examined), and after correction for age and sex, hearing function was normal in 5 of 19 families (7 cases examined). Age and severity of the myopathy did not have a clear relationship with the retinal vasculopathy or the hearing loss. There were no differences between families in which the myopathy was linked to chromosome 4q35 and families in which linkage could not be proven. Minimal retinal vascular changes and high tone hearing loss can be observed occasionally in the normal population. Therefore, although retinal vasculopathy and hearing loss are part of the clinical picture of FSHD, these signs cannot be accepted as decisive criteria for FSHD in clinically equivocal cases.

Adult↗
PubMed1995

Facioscapulohumeral muscular dystrophy in the Dutch population.

Extrapolating the figures from a previous study on FSHD in a province of The Netherlands to the entire Dutch population suggests that at present a nearly complete overview is obtained of all symptomatic kindred. In 139 families, dominant inheritance was observed in 97, a pattern compatible with germline mosaicism in 6, while sporadic cases were found in 36 families. A mutation frequency of 9.6% was calculated. Mental retardation and severe retinal vasculopathy were reported in low frequencies (1%). Early onset was seen more frequently in sporadic cases. Chromosome 4 linkage appeared excluded in 3 of 22 autosomal-dominant families. The clinical pictures in the linked and nonlinked families were identical.

Age of Onset↗
PubMed1995

High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.

A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been localized at 4q35. Subsequently, it was found that probe p13E-11 detects a polymorphic EcoRI fragment, usually > 28 kb, in normal individuals, whereas in sporadic and familial FSHD cases, an EcoRI fragment, usually < 28 kb, was found. Although these findings have been amply confirmed, several aspects are as yet either controversial or unsolved. In the present investigation, 34 Brazilian FSHD families were studied at the clinical and the molecular level for the following purposes: to assess the frequency of new mutations and their effect on estimates of biological fitness, to characterize FSHD-associated EcoRI fragments detected with probe p13E-11 in familial--as compared with isolated--FSHD cases, and to assess whether anticipation occurs in multigenerational families. Results from our study suggest that new mutations are apparently frequent for FSHD and may account for at least one-third of the cases, that somatic mosaicism may not be rare, and that biological fitness appeared to be reduced in FSHD, ranging from 0.6 to 0.82 by different estimates, with no difference in sexes. Interestingly, the size of the new EcoRI fragment is apparently smaller in more severely affected isolated patients. Moreover, the age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggests that anticipation occurs for FSHD in the majority of the families.

Adolescent↗