Search PubMed⌕ Search

Biomedical subjects

J L Weber

Publications and source records attributed to J L Weber.

At least 73 records · Page 4Linked to original sources
PubMed1995

Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p.

An autosomal dominant distal form of spinal muscular atrophy mainly affecting the upper limbs with a mean age of onset of 17 years has been identified in a large Bulgarian family. Linkage of the above family to the spinal muscular atrophy type I, II and III locus on chromosome 5 has been excluded. In an attempt to map this disease gene we have analysed individuals of this family, with more than 140 microsatellite polymorphic markers of the human genome. A maximum lod score of 5.99 at theta = 0.007 has been obtained with locus D7S795. We have thus mapped the gene for this hereditary form of distal spinal muscular atrophy to chromosome 7p.

Adolescent↗
PubMed1995

Nutrients, body composition and exercise are related to change in bone mineral density in premenopausal women.

This study determined relationships among total energy intake, nutrient intake, body composition, exercise group status, and annual rates of change (slopes) in bone mineral density in 66 Caucasian premenopausal women (mean age, 34.4 +/- 2.7) taking calcium supplements. Body composition components measured by dual-energy X-ray absorptiometry included fat mass, soft tissue lean mass, and bone mineral density (g/cm2) of total body, spine (lumbar vertebrae 2-4), and three femur sites measured at baseline, 5, 12, and 18 mo. Nutrients were not significant variables in regression models predicting bone mineral density slopes (rates of change) at any femur site. The only significant variable in models predicting Ward's triangle bone mineral density slope was the initial fat mass and, for trochanter, exercise. Significant variables (P < 0.05) in models predicting total body bone mineral density slope included the initial fat mass and fat mass slope plus either vitamin A, carotene, fiber, magnesium, or phosphorus (R2 from 0.31 to 0.25) and fat mass slope plus sodium (R2 = 0.24). The significant variable in the model predicting L2-4 slope was energy intake (R2 = 0.17, P < 0.05). We conclude that nutrient intake, exercise, and body composition are related to bone mineral density rate of change and that relations among these variables vary by bone site.

Absorptiometry, Photon↗
PubMed1995

Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.

Cerebral cavernous malformations (CCM) are vascular lesions present in some 20 million people worldwide that are responsible for seizures, migraine, hemorrhage, and other neurologic problems. Familial cases ofCCM can be inherited as an autosomal dominant disorder with variable expression. A gene for CCM (CCM/)was recently mapped to a 33-cM segment of chromosome 7q in a large Hispanic family (Dubovsky et al.1995). Here, the collection of several new short tandem repeat polymorphisms (STRPs) within the region of interest on 7q and the refinement of the marker order in this region using both linkage analysis in CEPH families and especially YAC-based STS content mapping are described. Affected members of three Hispanic families share allele haplotypes indicating a common ancestral mutation within these families. Using the shared haplotype information along with analysis of crossovers in affected individuals from both the Hispanic and Caucasian families, the region likely to contain the CCMI gene has been reduced to a 4-cM segment of 7q between D7S2410 and D7S689. All markers within the refined chromosomal segment were located on a single YAC contig estimated to be approximately 2 Mb in size. Four potential candidate genes have been mapped to this region.

Base Sequence↗
PubMed1995

Autosomal recessive retinitis pigmentosa locus maps on chromosome 1q in a large consanguineous family from Pakistan.

A large Pakistani family with several consanguineous marriages is described, in which autosomal recessive retinitis pigmentosa is segregating. Linkage studies revealed close linkage between the disease locus and six loci on chromosome 1q (D1S158, F13B, D1S422, D1S412, D1S413, and D1S53) with maximum lod scores ranging from 0.988-4.657 at theta = 0.065-0.235. However, the analysis of individual nuclear families showed very close linkage without recombination in three branches and several recombinants and negative lod scores throughout in the fourth branch. These results strongly suggest that mutations of two different genes are responsible for the disease in the 'linked' and 'unlinked' branches. Parallel to the linkage heterogeneity, clear phenotypic differences have been observed among the 'linked' and 'unlinked' parts. Our findings demonstrate that in case of recessive disorders the possibility of non-allelic genetic heterogeneity should always be considered, even within the same kindred and in genetic isolates if a largely extended pedigree is analysed.

Chromosome Mapping↗
PubMed1995

CEPH consortium map of chromosome 14.

Families from the linkage panel of Centre d'Etude du Polymorphisme Humain have been used to generate a linkage map containing 68 loci; 13 genes, 33 di- and 4 tetranucleotide repeats, one oligonucleotide ligation assay (OLA), and 17 RFLPs. This map integrates markers from several previous maps, and has undergone further error checking. 43 loci have been placed with odds of 1000:1 or greater, five with odds of 100:1, with an average interval of 3.5 cM. An additional 20 loci have been placed within defined intervals.

Chromosome Mapping↗
PubMed1994

Linkage analysis in familial melanoma kindreds to markers on chromosome 6p.

Malignant melanoma occurs as a familial cancer in 5%-10% of cases, where it segregates in a manner consistent with autosomal dominant inheritance. Evidence from cytogenetics, fine mapping studies of deletions in melanomas and recent linkage studies supports the location of a human melanoma predisposition gene on the short arm of chromosome 9. Evidence also exists for a melanoma gene on Ip, indicating genetic heterogeneity for melanoma predisposition. Previous studies have also reported findings suggestive of linkage of some melanoma families to the HLA region on the short arm of chromosome 6 (6p), indicating the possibility of even greater heterogeneity. To further define the possible effect of a gene within the HLA region on melanoma susceptibility, we have typed 7 simple tandem repeat polymorphisms (STRPs) from 6p in 16 Australian melanoma kindreds. Maximum 2-point LOD scores ranged from 1.13 (theta = 0.2) to 2.03 (theta = 0.15) for 4 contiguous markers flanking the HLA complex, and multi-point analysis gave a peak LOD score of 1.64, 24 centimorgans telomeric to D6S109. However, extended haplotype analysis of these markers showed that a region between D6S105 and HLAF segregated with melanoma in 5/16 families. These results are surprising given that the same cohort of families has previously been shown to be linked to chromosome 9. One interpretation of the current findings is that melanoma susceptibility in some families may result from a gene mapping within the HLA region of chromosome 6p.

Chromosome Mapping↗
PubMed1994

A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC).

In the last few years there have been rapid advances in developing genetic maps for humans, greatly enhancing our ability to localize and identify genes for inherited disorders. Through the collaborative efforts of three large groups generating microsatellite markers and the efforts of the 110 CEPH collaborators, a comprehensive human linkage map is presented here. It consists of 5840 loci, of which 970 are uniquely ordered, covering 4000 centimorgans on the sex-averaged map. Of these loci, 3617 are polymerase chain reaction-formatted short tandem repeat polymorphisms, and another 427 are genes. The map has markers at an average density of 0.7 centimorgan, providing a resource for ready transference to physical maps and achieving one of the first goals of the Human Genome Project--a comprehensive, high-density genetic map.

Chromosome Mapping↗
PubMed1994

Cloning, sequencing, and mapping of the human chromosome 14 heat shock protein gene (HSPA2).

A genomic clone for the human heat shock protein (HSP) 70 gene located on chromosome 14 was isolated and sequenced. The gene, designated HSPA2, has a single open reading frame of 1917 bp that encodes a 639-amino acid protein with a predicted molecular weight of 70,030 Da. Analysis of the sequence indicates that HSPA2 is the human homologue of the murine Hsp70-2 gene with 91.7% identity in the nucleotide coding sequence and 98.2% in the corresponding amino acid sequence. HSPA2 has less amino acid homology to other members of the human HSP70 gene family, 83.3% to the heat-inducible HSP70-1 gene and 86.1% with the human heat shock cognate gene HSC70. HSPA2 is constitutively expressed in most tissues, with very high levels in testis and skeletal muscle. Significant but lower levels are also expressed in ovary, small intestine, colon, brain, placenta, and kidney. A yeast artificial chromosome (YAC) clone containing HSPA2 (YAC741H4) that also contained the polymorphic marker D14S63 was identified. This 670-kb YAC was mapped to 14q24.1 by fluorescence in situ hybridization (FISH). Subsequent two-color FISH and genetic mapping placed HSPA2/D14S63 proximal to the markers D14S57 and D14S77.

Amino Acid Sequence↗
PubMed1994

Integrated mapping analysis of the Werner syndrome region of chromosome 8.

The Werner syndrome locus (WRN) is located at 8p11-p12. To facilitate eventual cloning of the WRN gene, a 10,000-rad radiation-reduced hybrid (RH) cell panel was generated to map genetic markers, sequence-tagged sites (STSs), and genes in this region. A hamster cell line carrying an intact human chromosome 8 was fused with another hamster cell line. Two sets of hybrid cell panels from 2 separate fusions were generated; each panel consisted of 50 independent clones; 33 and 34 cell lines from the 2 fusions retained human chromsome material as determined by inter-Alu PCR. The combined panel was genotyped for 52 markers spanning the entire chromosome, including 10 genes, 29 anonymous polymorphic loci, and 13 STSs. Seventeen of these markers have not been previously described. Markers near the centromere were retained at a higher frequency than more distal markers. Fluorescence in situ hybridization was also used to localize and order a subset of the markers. A RH map of the WRN region was constructed using a maximum likelihood method, giving the following most likely order: D8S131-D8S339 (GSR)-D8S124-D8S278-D8S259-(D8S71)-D8S283- D8S87-D8S105-D8S135 (FGFR1)-D8S135PB-D8S255-ANK1. A genetic map of 15 short tandem repeat polymorphic loci in the WRN region was also constructed. The marker orders from the genetic and RH maps were consistent. In addition, an integrated map of 24 loci in the WRN region was generated using information from both genetic and RH mapping methods. A 1000:1 framework map for 6 loci (LPL-D8S136-D8S137-D8S87-FGFR1-ANK1) was determined by genetic mapping, and the resulting locus order was fixed during analysis of the RH genotype data. The resulting integrated map contained more markers than could confidently be ordered by either genetic or RH mapping alone.

Base Sequence↗
PubMed1994

Comparison of fluorescence-based semi-automated genotyping of multiple microsatellite loci with autoradiographic techniques.

The practical application of highly efficient fluorescence-based methods for the semi-automated genotyping of polymerase chain reaction-based microsatellite markers will depend on the development of robust protocols that provide accurate and reproducible data. In the present report we compare the accuracy of a fluorescence-based protocol with a benchmark radiolabeling method that depends on a known sequence ladder or amplified DNA from reference individuals for sizing by autoradiography. Three microsatellite markers, IGF1 (mfd 1), D4S174 (mfd 59), and D5S211 (mfd 154), with products overlapping in size were each labeled with a different fluorophore and run simultaneously with an internal size standard in a single electrophoretic lane. The size of each allele was compared for these markers by using both techniques for five larger CEPH families (884, 1331, 1332, 1333, and 1362). Of 462 possible alleles, four discrepancies (0.8%) were identified when the two approaches were compared. We conclude that the fluorescence-based protocol is at least as accurate as the standard radiolabeling technique since none of the sizing errors arose as a result of the fluorescence-based technique. We describe the adaptation of this fluorescence-based protocol to the simultaneous analysis of up to 24 microsatellite loci per electrophoretic lane. These highly accurate and efficient semi-automated techniques will be useful in high-resolution genomic analyses.

Alleles↗
PubMed1994

Genetic mapping of the human growth hormone-releasing factor gene (GHRF) using two intragenic polymorphisms detected by PCR amplification.

We have analyzed the human growth hormone-releasing factor (GHRF) gene by high-resolution restriction mapping of its PCR amplification products. Two intragenic PCR fragment length polymorphisms (PCRFLPs) were detected in introns A and C of the GHRF gene, whose heterozygosities are 40 and 7%, respectively. Linkage analysis using the CEPH panel showed that GHRF is linked to several markers on chromosome 20 and assigned the GHRF locus to a region near the centromere between D20S27 (assigned to 20p12.1-p11.23) and D20S16 (assigned to 20q12). These intragenic PCRFLPs and the tightly linked polymorphisms should provide useful markers for linkage studies of GHRF alleles in familial disorders of growth such as isolated growth hormone deficiency.

Base Sequence↗
PubMed1994

Mapping of short tandem repeat polymorphisms on human chromosome 3.

Linkage analysis was used to determine map positions for 18 short tandem repeat polymorphisms that continuously span 186 cM of human chromosome 3. Mapping was based on the genotyping of 40 CEPH reference families. Loci order from pter-qter was D3S1252-D3S1235-D3S1234-D3S1233- D3S1254-D3S1251-D3S1215-RHO-ACPP- D3S1238-D3S1206-D3S196-D3S1237- (D3S1253,D3S1439)-D3S1243-D3S1232-SST. Odds against inversion of adjacent markers in all cases were 700:1 or better, except for the marker pair at D3S1253,D3S1439 that was not separated by any recombinants and therefore could not be ordered. Only one gap greater than 25 cM on the sex-equal map was observed.

Base Sequence↗
PubMed1994

Homozygosity mapping of the Werner syndrome locus (WRN).

Werner syndrome (WS) is an autosomal recessive disorder characterized by the early onset of several age-related diseases. The locus for this disease was recently mapped to 8p12. We studied 27 WS kindreds of mixed ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of "definite" WS and affected subjects in the remaining 3 pedigrees were given the diagnosis of "probable" WS. Affected subjects from each kindred were genotyped for 13 short tandem repeat polymorphic sites. Two-point linkage analysis yielded significant evidence for linkage to D8S137, D8S339, D8S87, PLAT, D8S165, and D8S166. The locus yielding a maximum lod score at the smallest recombination fraction was D8S339, suggesting that this marker is the closest to the WS gene (WRN locus) of those tested. D8S339 gave significant lod scores (Zmax > or = 3.0) for both Japanese and non-Japanese (mostly Caucasian) families, demonstrating that a single locus is responsible for WS in both groups. Multipoint analysis of these markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. The combined evidence from 2-point analysis, multipoint analysis, and analysis of regions of homozygosity in subjects from inbred pedigrees indicates that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339.

Alleles↗
PubMed1994

Integrated human genome-wide maps constructed using the CEPH reference panel.

High resolution linkage maps have proven to be invaluable tools in genetic investigations. We have assembled a collection of genetic maps constructed from primary data collected from investigators performing genotyping using the Centre Etude Polymorphism Humain (CEPH) reference pedigree panel. These maps were constructed using a rigorous, semi-automated map construction algorithm that evaluates the integrity of the maps during construction. Two classes of maps were produced: a high confidence "skeletal" set composed of 544 PCR based markers, and a more highly annotated "framework" set containing maps of 1,123 markers. Genetic map locations within the framework maps are provided for an additional 1,758 loci without statistically unique interval assignments.

Algorithms↗
PubMed1994

Know thy genome.

Explore the source record for details and available documents.

Alleles↗
PubMed1994

Genetic linkage of familial expansile osteolysis to chromosome 18q.

Familial expansile osteolysis is a rare bone dysplasia which is transmitted as an autosomal dominant trait in a large kindred in Northern Ireland. The gene which causes the disease shows tight linkage with several polymorphic markers on chromosome 18q with a maximum lod score of 11.53 at a recombination fraction of 0.00 with D18S64. The gene is flanked by D18S35 and D18S61 and is located at chromosome 18q21.1-q22. Mapping a new locus for a gene involved in regulation of bone metabolism may also have implications in the study of Paget's disease of bone which is a common related bone dysplasia.

Animals↗
PubMed1993

Genetic mapping of a locus predisposing to human colorectal cancer.

Genetic linkage analysis was used to determine whether a specific chromosomal locus could be implicated in families with a history of early onset cancer but with no other unique features. Close linkage of disease to anonymous microsatellite markers on chromosome 2 was demonstrated in two large kindreds. The pairwise lod scores for linkage to marker D2S123 in these kindreds were 6.39 and 1.45 at zero recombination, and multipoint linkage with flanking markers resulted in lod scores of 6.47 and 6.01. These results prove the existence of a genetically determined predisposition to colorectal cancer that has important ramifications for understanding and preventing this disease.

Chromosome Mapping↗