Gene/Protein Disease Symptom Drug Enzyme Compound
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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.
Hum Mol Genet 1993 Oct
PMID:Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E-11. 790 81

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.
Hum Mol Genet 1994 Aug
PMID:Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. 798 4

A gene responsible for an autosomal recessive form of limb girdle muscular dystrophy (LGMD2, MIM number 253600) has been localized on chromosome 15. After genotyping additional markers of this chromosome, two were found to flank the disease locus within an interval that was assessed as 7 centiMorgans. The screening of the CEPH YAC libraries with the corresponding probes allowed the isolation of YACs which were used in fluorescence in situ hybridization to define the LGMD2 cytogenetic interval as 15q15.1-15q21.1. Four different approaches were pursued for the establishment of the physical map of this area which allowed the assembly of an uninterrupted YAC contig spanning an estimated 10-12 megabases, with an average STS resolution of 140 kb or for the 25 polymorphic microsatellites on this map, of 400 kb. Twelve genes and 25 genetic markers were positioned in this contig, which is constituted of a minimum of 10 clones.
Hum Mol Genet 1994 Feb
PMID:Mapping of a chromosome 15 region involved in limb girdle muscular dystrophy. 800 96

We report the construction and characterization of a region-specific microdissection library for human chromosome 2p11-p13. This library (designated 2P4 library) is large, comprising 600,000 recombinant microclones. Thirty to 40% of the clones contain unique sequences. The insert sizes range from 100 to 800 bp, with a mean of 380 bp. A subset of the microclones was selected, based on their weak or no hybridization to total human DNA, for further analysis. Of 50 single-copy microclones analyzed, 35 clones (70%) were derived from human and are chromosome 2-specific. The insert sizes and the hybridizing genomic HindIII fragments of these clones were also determined. The 2P4 microdissection library and the single-copy microclones from the library are useful in preparing STS (sequence-tagged site) to isolate corresponding YAC (yeast artificial chromosome) or other clones with large inserts and for isolating region-specific cDNA clones as candidate genes for cloning disease-related genes assigned to this region.
Somat Cell Mol Genet 1994 Mar
PMID:Region-specific microdissection library and single-copy microclones for human chromosome 2p11-p13. 800 66

Chalcone (CHS) and stilbene (STS) synthases are related plant-specific polyketide synthases that are key enzymes in the biosynthesis of flavonoids and of stilbene phytoalexins, respectively. A phylogenetic tree constructed from 34 CHS and four STS sequences revealed that the STS formed no separate cluster but grouped with CHS from the same or related plants. This suggested that STS evolved from CHS several times independently. We attempted to stimulate this by site-directed mutagenesis of an interfamily CHS/STS hybrid, which contained 107 amino acids of a CHS from Sinapis alba (N-terminal) and 287 amino acids of a STS from Arachis hypogaea. The hybrid had no enzyme activity. Three amino acid exchanges in the CHS part (Gln-100 to Glu, Val-103 to Met, Val-105 to Arg) were sufficient to obtain low STS activity, and one additional exchange (Gly-23 to Thr) resulted in 20-25% of the parent STS activity. A kinetic analysis indicated (1) that the hybrids had the same Km for the substrate 4-coumaroyl-CoA but a lower Vmax than the parent STS, and (2) that they had a different substrate preference than the parent STS and CHS. Most of the other mutations and their combinations led to enzymatically inactive protein aggregates, suggesting that the subunit folding and/or the dimerization was disturbed. We propose that STS evolved from CHS by a limited number of amino acid exchanges, and that the advantage gained by this enzyme function favored the selection of plants with improved STS activity.
J Mol Evol 1994 Jun
PMID:Evidence that stilbene synthases have developed from chalcone synthases several times in the course of evolution. 808 86

We have constructed a YAC contig containing 54 clones and a minimum of 7 Mbp of human DNA, that maps to bands q34-35 on chromosome 5. The contig was nucleated using FISH mapped cosmid clones shown to flank the t(2;5)(p23;q35) translocation breakpoint in a CD30-positive large cell lymphoma cell line. Thirty of the 54 YAC clones are non-chimeric and six span the translocation breakpoint, as determined by FISH analysis. A total of 28 YAC clone end fragments, 14 non-polymorphic YAC end STS probes and 13 polymorphic microsatellite STS markers have been used to order clones within the contig. The most distal genetic markers (D5S498 and D5S619) are separated by 15 cM based on multipoint linkage analysis. This map of overlapping clones and the set of densely spaced physical markers will promote our understanding of the 5q34-35 region and its associated genes.
Hum Mol Genet 1994 Jan
PMID:Construction of a YAC contig and a STS map spanning at least seven megabasepairs in chromosome 5q34-35. 816 60

The pericentric inversion of chromosome 16 and the t(16;16) are two recurrent aberrations in bone marrow of patients with acute nonlymphocytic leukemia subtype M4 Eo, characterized by abnormal eosinophilic granulation. We describe here the precise localization of the breakpoints using fluorescence in situ hybridization (FISH) with cosmids spread over the short arm of chromosome 16 and the detection, isolation and characterization of a 14Kb EcoRI fragment containing a cluster of breakpoints. First, cosmids were mapped to intervals defined by constitutional 16p rearrangements, second, the inv(16) and t(16;16) breakpoints were mapped to one of the intervals using FISH with the mapped cosmids and third, cosmids within this interval were ordered using two color interphase FISH. An STS of the cosmid closest to the breakpoints was then used to isolate five YACs, which did span all of the 16 inv(16) breakpoints and one t(16;16) breakpoint analysed. In the DNA of one inv(16) patient we detected an additional submicroscopic deletion immediately proximal to the 16p breakpoint. Since this patient has the same phenotype, the 16p sequences proximal to the breakpoint seem non-essential to M4 Eo. This implies that the pathologic event is the juxtaposition of sequences distal to the 16p breakpoint with sequences proximal to the 16q breakpoint. While four of the five YACs showed instability of the region around the inv(16) breakpoint, DNA halo analysis allowed us to identify one YAC which was co-linear with normal genomic DNA and has yielded the actual breakpoint sequences which could be subcloned into cosmids and fosmids.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1993 Oct
PMID:Cloning the breakpoint cluster region of the inv(16) in acute nonlymphocytic leukemia M4 Eo. 826 4

The juxtacentromeric region of the human chromosome 17 short arm (17p11.2-p12) contains genes involved in the Charcot-Marie-Tooth type 1A disease (CMT1A) and the Smith-Magenis syndrome (SMS). CMT1A is associated with a duplication of a short segment whereas SMS is linked to microdeletions, extending toward the centromere. We describe the construction and analysis of a 5 Mb YAC contig spanning the CMT1A duplicated segment and the distal part of four SMS microdeletions. We concluded that the YAC contig contains about 1Mb of genomic DNA which is deleted in the four SMS patients analysed. Moreover two YACs contain both STS deleted in SMS (U3) and STS duplicated in CMT1A (5H5), but the proximal breakpoint associated with the CMT1A duplication is not the same as the distal SMS breakpoint we studied. Finally we located five new STS in SMS deletion. Two of them, a microsatellite (D17S805(23)) and the gene coding for small nuclear RNA U3, have been localized in the contig we described. We may also note that snU3 is the first expressed sequence localized in an SMS deletion so far. The possible participation of this gene in the SMS phenotype is discussed.
Hum Mol Genet 1993 Aug
PMID:Relationship between Charcot-Marie-Tooth 1A and Smith-Magenis regions. snU3 may be a candidate gene for the Smith-Magenis syndrome. 840 6

We have undertaken a detailed analysis of several hundred YACs from widely available YAC libraries which map to human chromosome 21 with the goal of improving the physical map of chromosome 21 and determining the feasibility of producing a minimal tiling path of well characterized, stable, non-chimeric YACs spanning the long arm of the chromosome (21q). We report information on over 500 YACs known to contain STS from 21q including information on size, stability, chimerism, marker content, and NotI restriction sites. YACs derive from the CEPH and St. Louis YAC libraries, and STSs include the set of 198 markers originally used do assemble a YAC contig of 21q, as well as additional anonymous probes and gene markers. This information has assisted in refinements of STS order, has defined a region of general instability in 2lq22.3, has identified an increased number of NotI restriction sites, and has defined cryptic gaps, particularly in 2lq2l, for which few or no markers are available. These results have allowed us to develop and assess a minimal tiling path of overlapping YACs consisting of 59 YACs (and two PI clones), largely non chimeric, stable, and of verified STS content. They total 30 mb of non-overlapping DNA, and contain all chromosome 21 specific STSs originally used to define the 810 YAC 21q YAC contig. When integrated with the analysis of a somatic cell hybrid mapping panel of chromosome 21 reported in the accompanying manuscript, a greatly enhanced understanding of the physical map of chromosome 21 is obtained.
Somat Cell Mol Genet 1995 Nov
PMID:YAC analysis and minimal tiling path construction for chromosome 21q. 860 May 68

Rodent-human somatic cell hybrids containing single human chromosomes or chromosome fragments are extremely valuable in physical mapping, marker analysis, and disease mapping. Chromosome 21 has been extensively studied in this fashion, and a single set of hybrids has been utilized in mapping the majority of chromosome 21 markers. The utility of a set of hybrids depends upon the definition of the human chromosome content. Recently, Chumakov and coworkers (1) utilized 198 chromosome 21 markers in the preliminary analysis of YACs spanning chromosome 21q. We have used these same markers to evaluate the STS content of a set of 27 chromosome 21 somatic cell hybrids, resulting in the description of the breakpoints at the molecular level, as well as the definition of 35 "bins. " The detailed molecular definition of chromosome 21 content of the hybrids, in combination with the further analysis of chromosome 21 YACs (2), has resulted in the most detailed picture of chromosome 21 to date.
Somat Cell Mol Genet 1995 Nov
PMID:Molecular analysis and breakpoint definition of a set of human chromosome 21 somatic cell hybrids. 860 May 69


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