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C Wijmenga

Publications and source records attributed to C Wijmenga.

At least 73 records · Page 4Linked to original sources
PubMed1994

Pulsed-field gel electrophoresis of the D4F104S1 locus reveals the size and the parental origin of the facioscapulohumeral muscular dystrophy (FSHD)-associated deletions.

Recently, probe p13E-11 (D4F104S1) was shown to identify de novo DNA rearrangements, which are associated with the development of facioscapulohumeral muscular dystrophy (FSHD). These rearrangements are likely to become instrumental in cloning the FSHD gene itself. Analysis by pulsed-field gel electrophoresis demonstrates that p13E-11 recognizes two highly polymorphic loci, with HindIII restriction fragments ranging in size from about 30 to 320 kb. Haplotype analysis unambiguously assigned one of the two loci to chromosome 4q35. The detection of identical NotI or NruI fragments with both CEB8 (D4F35S1) and p13E-11 demonstrated that the DNA rearrangements are deletions that are restricted to the HindIII fragments detectable by p13E-11. In two cases, the sizes of the deletion could be established and were found to be 25 and 85 kb in length, respectively. So far, we have been able to define the parental origin of the mutation in seven different patients and have found that in five cases the maternal allele was involved.

Chromosomes, Human, Pair 4↗
PubMed1994

Facioscapulohumeral muscular dystrophy in early childhood.

OBJECTIVE: To determine the occurrence and the clinical and genetic variability of early-onset facioscapulohumeral muscular dystrophy (FSHD). DESIGN: Patients were derived from a large series of patients who participated in a genetic study of FSHD in the Netherlands. PATIENTS: A group of 96 patients of 17 families with autosomal dominant FSHD, nine sporadic cases of FSHD, and 35 children at risk for having the FSHD gene was searched for the presence of early-onset cases. Criteria for early-onset FSHD were (1) signs or symptoms of facial weakness before the age of 5 years and (2) signs or symptoms of shoulder girdle weakness before the age of 10 years. RESULTS: Six early-onset cases (four familial, two sporadic) were identified. Four of five cases showed an abnormal DNA fragment with the probe p13E-11, which has been shown to detect DNA rearrangements in FSHD patients. The clinical symptoms in these early-onset cases showed great variability with respect to rate of progression of muscle weakness, the association of hearing loss and retinopathy, and the expression of the disorder in parents and siblings. CONCLUSIONS: Infantile FSHD has been suggested to be a separate form of the disease, often accompanied by sensorineural hearing loss and retinal telangiectasia. Our findings, as well as the fact that both hearing loss and retinal vasculopathy have been recently shown to be part of FSHD, suggest that early-onset FSHD is not a separate entity, but part of a wide clinical spectrum of FSHD.

Adolescent↗
PubMed1994

Chromosome 4q35 haplotypes and DNA rearrangements segregating in affected subjects of 19 Italian families with facioscapulohumeral muscular dystrophy (FSHD).

Four DNA markers on the distal long arm of chromosome 4 have been analyzed for their linkage to facioscapulohumeral muscular dystrophy locus (FSHD) in a series of 16 Italian families. We found that, in two families, the disease is not linked to the 4q35 markers, indicating the presence of genetic heterogeneity among Italian FSHD families. Linkage analysis in the remaining families supports the order cen-D4S171-D4S163-D4S139-D4S810-FSHD-qter, in agreement with the physical map from the literature. EcoRI digestion and hybridization with the distal marker p13E-11 (D4S810)1 detected DNA rearrangements in the affected members of both sporadic and familial cases of FSHD, with family-specific fragments ranging in size between 15 kb and 28 kb. In three sporadic FSHD cases, the appearance of a new "small" fragment not present in either parent was clearly associated with the development of FSHD disease. However, in the familial cases analyzed, we observed two recombinations between all four 4q35 markers and the disease locus in apparently normal subjects, leaving open the possibility of nonpenetrance of the FSHD mutation.

Adolescent↗
PubMed1994

Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.

The sequence of the tandem repeat sequence (D4Z4) associated with facioscapulohumeral muscular dystrophy (FSHD) has been determined: each copy of the 3.3 kb repeat contains two homeoboxes and two previously described repetitive sequences, LSau and a GC-rich low copy repeat designated hhspm3. By Southern blotting, FISH and isolation of cDNA and genomic clones we show that there are repeat sequences similar to D4Z4 at other locations in the human genome. Southern blot analysis of primate genomic DNA indicates that the copy number of D4Z4-like repeats has increased markedly within the last 25 million years. Two cDNA clones were isolated and found to contain stop codons and frameshifts within the homeodomains. An STS was produced to the cDNAs and analysis of a somatic cell hybrid panel suggests they map to chromosome 14. No cDNA clones mapping to the chromosome 4q35 D4Z4 repeats have been identified, although the possibility that they encode a protein cannot be ruled out. Although D4Z4 may not encode a protein, there is an association between deletions within this locus and FSHD. The D4Z4 repeats contain LSau repeats and are adjacent to 68 bp Sau3A repeats. Both of these sequences are associated with heterochromatic regions of DNA, regions known to be involved in the phenomenon of position effect variegation. We postulate that deletion of D4Z4 sequences could produce a position effect.

Amino Acid Sequence↗
PubMed1993

The human skeletal muscle adenine nucleotide translocator gene maps to chromosome 4q35 in the region of the facioscapulohumeral muscular dystrophy locus.

Facioscapulohumeral muscular dystrophy (FSHD) is a relatively common autosomal dominant neuromuscular disorder. The gene for FSHD has recently been assigned to chromosome 4q35. Although abnormal mitochondrial and biochemical changes have been observed in FSHD, the molecular defect is unknown. In addition to the FSHD gene, the human muscle adenine nucleotide translocator gene (ANT1) is located on chromosome 4. Interestingly, biochemical studies recently showed a possible defect of ANT1. In order to evaluate the potential role of ANT1 in the etiology of FSHD, the human ANT1 gene was isolated by cosmid cloning and localized to 4q35, in the region containing the FSHD gene. However, in situ hybridization and physical mapping of somatic cell hybrids localized the ANT1 gene proximal to the FSHD gene. In addition, a polymorphic CA-repeat 5 kb upstream of the ANT1 gene was used as a marker in FSHD and Centre d'Etude du Polymorphisme Humain families to perform linkage analysis. These data together exclude ANT1 as the primary candidate gene for FSHD. The most likely order of the loci on chromosome 4q35 is cen-ANT1-D4S171-F11-D4S187-D4S163-D4S139-+ ++FSHD-tel.

Animals↗
PubMed1993

Facioscapulohumeral muscular dystrophy: the impact of genetic research.

Recent developments in genetic research have led to the localization and identification of the causative gene defect in a large number of neurological diseases. This paper describes some of the basic principles of molecular genetics and the strategies that have been followed in the search for the gene for facioscapulohumeral muscular dystrophy (FSHD), beginning with the recent localization to chromosome 4q. Many questions remain concerning the pathogenesis and possible genetic heterogeneity of this autosomal dominant myopathy. Hitherto, most evidence favours a genetically homogeneous disorder, but only the isolation and detailed characterization of the FSHD gene will resolve these issues completely.

Chromosome Aberrations↗
PubMed1993

Linkage and apparent heterogeneity in proximal spinal muscular atrophies.

Linkage studies with 9 highly informative DNA markers on the long arm of chromosome 5 were performed in 12 multiplex families (29 patients) with spinal muscular atrophy (SMA) from The Netherlands. The results of the linkage analysis were compatible with localization of a major SMA gene in the chromosomal region 5q12-13. By minimum recombinant analysis the most likely position of the SMA locus was between loci D5S6/D5S125 and D5S112/MAP1B, which is in agreement with several linkage studies from other countries. In four families, however, more than one crossover between SMA and a flanking DNA marker appeared, and in one family the observed hybridization phenotype for the markers closely flanking the SMA locus was identical for an unaffected individual and for his two affected sibs with SMA type III. For this latter family, among several explanations the most likely are either the presence of a double crossover or linkage heterogeneity.

Chromosome Mapping↗
PubMed1993

Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromsome 4q35 recombination events.

A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been linked to polymorphisms on chromosome 4q35. Multipoint linkage analyses have placed this gene distal to all reported genetic markers on the chromosome. By using as a probe a clone isolated from a cosmid containing sequences related to a homeobox domain, de novo DNA rearrangements were reported in sporadic and familial cases of FSHD. Linkage analysis of an EcoRI polymorphism detected by this clone in twenty-four multigenerational FSHD families revealed recombinants between this marker and the disease with a recombination fraction of 0.05. Two families with apparent germline mosaicism were also identified.

Blotting, Southern↗
PubMed1993

Physical mapping and YAC-cloning connects four genetically distinct 4qter loci (D4S163, D4S139, D4F35S1 and D4F104S1) in the FSHD gene-region.

We have constructed a long-range restriction map of the region on chromosome 4q that contains the gene for facioscapulohumeral muscular dystrophy (FSHD). This region contains the linkage group cen ... D4S163-D4S139-D4F35S1-D4F104S1-FSHD ... 4qter, which spans a genetic distance of about 5 cM. Pulse field gel electrophoresis (PFGE) mapping indicated that these loci span a region not more than 1 Mb. STSs were developed for several of these loci, which served to isolate four overlapping yeast artificial chromosomes (YACs). These YACs confirmed the PFGE map and have allowed us to generate a more detailed restriction map using cosmid contig mapping. The physical distances were smaller than was expected on the basis of the genetic map. Two potential HTF islands have been detected within the cloned region. One HTF island maps about 100 kb centromeric from the tandem repeats involved in the FSHD mutation, whereas the other maps within these tandem repeats.

Base Sequence↗
PubMed1993

Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E-11.

We have produced a fine restriction map around the locus D4F104S1 (previously designated D4S810); a probe to this locus, p13E-11, identifies a polymorphic EcoRI fragment containing 3.2kb tandem repeats and detects DNA rearrangements associated with facioscapulohumeral muscular dystrophy (FSHD). We developed an STS (D4F106S1) which maps 2kb proximal to D4F104S1, and used this to isolate a 470kb YAC (y25C2E) from the ICI YAC library and a 930kb YAC (y956A11) from the CEPH megabase library. Both YACs contain the loci D4S139, D4F35S1 and D4F104S1. A cosmid library was produced from YAC y25C2E and two cosmid contigs constructed; a 115kb contig encompassing D4S139, and one of 135kb linking D4F35S1 and D4F104S1 and extending distal to the EcoRI fragment detected by p13E-11. A fine restriction map of both these contigs has been generated, allowing the orientation of the EcoRI fragment rearranged in FSHD to be determined. YAC y956A11 was used to confirm the integrity of y25C2E and the map of this region. 9B6A, a probe to the homeobox region of the tandem repeat D4Z4, identified a cross-hybridising sequence proximal to D4F104S1, however, p13E-11 does not detect this additional locus. CpG islands were identified between D4S139 and D4F35S1 and within each copy of the tandem repeat. The probe 9B6A detected each copy of the repeat motif, suggesting there is homeobox present in every copy of the 3.2kb repeat.

Base Sequence↗
PubMed1993

FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit.

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder characterized by progressive weakness of the facial, shoulder and upper arm muscles. The disease is associated with DNA rearrangements which are detectable using probe p13E-11 (D4F104S1) in DNA digested with EcoRI or other restriction enzymes. We have cloned and characterized the rearranged EcoRI fragment of four unrelated FSHD patients. Restriction fragment mapping and DNA sequence analysis showed that the proximal and distal parts of the EcoRI fragment, which flank a region of tandemly repeated 3.2 kb units, are identical in normal and rearranged EcoRI fragments. These results strongly support the hypothesis that the FSHD associated rearrangements are due to deletions of integral copies of the 3.2 kb repeated unit. Since these repeated units are likely to form part of the FSHD transcription unit, the variation in repeat unit number might affect the function of the gene product. Hence, our data confine the FSHD gene region and thus provide a starting point for cloning the FSHD gene.

Arm↗
PubMed1993

No evidence of genetic heterogeneity in Brazilian facioscapulohumeral muscular dystrophy families (FSHD) with 4q markers.

The gene responsible for facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant neuromuscular condition, has been mapped to chromosome 4. Until recently, the two closest available markers were D4S139 and D4S163 but a new marker (p13E-11) which recognizes de novo rearrangements in isolated cases of FSHD characterized by shorter EcoRI fragments has been now identified. Linkage analysis in FSHD families with p13E-11 shows that usually a smaller fragment segregates with the disease gene among the affected individuals from each genealogy. In the present paper, we report the results from linkage analysis with the marker loci D4S163 and D4S139 in 6 FSHD families and with p13E-11 in these and in 6 other additional Brazilian families (total of 12). The results from such analysis do not suggest genetic heterogeneity for FSHD in our population. In 11 out of the 12 families studied with p13E-11, a shorter specific EcoRI band was found to segregate in all affected patients from each genealogy. In one family, the normal individuals had a smaller EcoRI fragment than the affected ones. The size of the EcoRI fragments detected with p13E-11 varied from 13.5 to 29 kb but was constant within each genealogy. Our results suggest that the use of the marker p13E-11 for preclinical and prenatal diagnosis should be done only in families in which it is possible to identify the fragments segregating among the affected individuals.

Adolescent↗
PubMed1993

Molecular analysis of British facioscapulohumeral dystrophy families for 4q DNA rearrangements.

Facioscapulohumeral muscular dystrophy is an important autosomal dominant neuromuscular disorder that has been localised to 4q35. We have analysed our extensive panel of 45 families with a new DNA marker p13E-11. The findings, based on multiply informative individual meioses and multipoint mapping, suggest that probe p13E-11 is the closest marker for the disorder and it is likely to be located proximal to the disease locus as are all the other present markers. In nine of the ten new mutations studied, a new smaller EcoRI fragment which was not present in either of the parents was detected, indicating that a de novo DNA rearrangement is indeed associated with the development of the disease state. However, in view of the difficulty in defining the size of over 30kb alleles and the recombinant events observed with p13E-11, we suggest that it should be used in combination with another VNTR marker until a close distal flanking marker for this condition is identified or the gene itself is isolated.

Adult↗
PubMed1992

Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder which maps to chromosome 4qter, distal to the D4S139 locus. The cosmid clone 13E, isolated in a search for homeobox genes, was subsequently mapped to 4q35, also distal to D4S139. A subclone, p13E-11, detects in normal individuals a polymorphic EcoRI fragment usually larger than 28 kilobases (kb). Surprisingly, using the same probe we detected de novo DNA rearrangements, characterized by shorter EcoRI fragments (14-28 kb), in 5 out of 6 new FSHD cases. In 10 Dutch families analysed, a specific shorter fragment between 14-28 kb cosegregates with FSHD. Both observations indicate that FSHD is caused by independent de novo DNA rearrangements in the EcoRI fragment detected by p13E-11.

Base Sequence↗
PubMed1992

Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium.

Members of an international consortium for linkage analysis of the facioscapulohumeral muscular dystrophy (FSHD) gene have pooled data for joint analyses, in an attempt to determine the precise location of the FSHD gene and the order of four DNA markers on 4q35 region. Six laboratories determined a total of 3,078 genotypes in 65 families, consisting of a total of 504 affected subjects and 559 unaffected subjects. For each marker, a mean of 648 meioses were informative. D4S139 and D4S163 were identified as the closest linked markers to the FSHD locus, with 99% upper confidence intervals of recombination fractions of .08 and .10, respectively. We have used the CRI-MAP program to construct the most likely order of cen-D4S171-F11-D4S163-D4S139-FSHD-tel, with favorable odds of 10(8)-10(114) over all other orders except that in which F11 and D4S171 are reversed, for which the odds ratio was 191:1. With this order, the genetic map of this region extends 25.5 cM in males and 13.8 cM in females (averaging 19.5 cM for sexes combined); the sex difference was statistically significant (P = .0013). Comparison between families for the two-point and multipoint lod scores involving FSHD showed no evidence for heterogeneity of this disorder. However, after the completion of this analysis, one large family which might show heterogeneity was identified. In view of this and the fact that all of the linked markers reside on the same side of the FSHD locus, the clinical application of these markers is not recommended at this time.

Chromosome Mapping↗