We examined chorea-free subjects at risk for Huntington's disease (n = 52) for lifetime psychiatric diagnoses, present mood, genetic marker status, and caudate glucose metabolic rates with positron ...emission tomography. Based on previous work, a caudate-ipsilateral hemisphere ratio less than 1.15 was defined as abnormal and predictive of Huntington's disease. None of three methods used to segregate subjects into groups more and less likely to develop Huntington's disease gave significant group rate differences for any formal psychiatric diagnoses. On present mood testing, however, subjective "anger/hostility" was significantly higher in those likely, compared with those less likely, to develop Huntington's disease, as determined by all three methods.
A human genomic DNA fragment in phage lambda containing FSHB, the gene for the beta-subunit of human follicle-stimulating hormone (FSH-beta), was analyzed and the nucleotide sequence of the region of ...the clone encoding FSH-beta was determined. A subclone of the lambda phage containing 67% of FSH-beta coding sequence was used as hybridization probe to determine the human chromosomal location of FSHB. A panel of mouse-human somatic cell hybrids containing reduced numbers of human chromosomes was screened with the FSHB probe; complete cosegregation of FSHB with human chromosome 11 was observed in all 26 cell hybrids tested. Analysis of a set of cell hybrids containing translocated derivatives of chromosome 11 further localized FSHB to the human chromosome region 11p11.2---11pter. A Hind III restriction fragment length polymorphism (RFLP) detected by another subclone of the lambda phage containing FSHB now provides a genetic marker for this region of the human genome.
We have identified and characterized 40 DNA probes detecting restriction fragment length polymorphism (RFLP) on human chromosome 4. Single copy human clones were isolated from a bacteriophage library ...enriched for chromosome 4 sequences. Each clone was hybridized to somatic cell hybrid DNAs for verification of its species and chromosomal origin and for regional localization. Sequences specific for chromosome 4 were tested for their ability to detect RFLPs in human DNA and their potential utility as genetic markers was assessed. Approximately 263,000 base pairs or 0.13% of the chromosome was screened for sequence variation. The estimate of heterozygosity calculated from this large body of data, H = 0.0021, indicates that the degree of sequence variation on chromosome 4 is comparable to other autosomes. The characterization of these 40 markers has tripled the number of polymorphic loci available for linkage studies on chromosome 4, making it feasible to begin construction of a detailed linkage map that will span the entire chromosome.
Recombinant DNA techniques have provided the means to generate large numbers of new genetic linkage markers. This technology has been used to identify a DNA marker that coinherits with the ...Huntington's Disease (HD) gene in family studies. The HD locus has thereby been mapped to human chromosome 4. The discovery of a genetic marker for the inheritance of HD has implications both for patient care and future research. The same approach holds considerable promise for the investigation of other genetic diseases, including Dystonia Musculorum Deformans.
alpha-L-iduronidase (IDUA), which when deficient causes mucopolysaccharidosis type I, is located near the Huntington disease locus (HD) on human Chromosome (Chr) 4p16.3, approximately 10(6) base ...pairs (bp) from the telomere. As part of our continuing efforts to define a detailed comparative map for this chromosomal segment in mice and humans, we have used an interspecific backcross between C57BL/6J and an inbred strain derived from Mus spretus to map Idua, the mouse homolog of IDUA. We also mapped the mouse homolog of D4S115, an anonymous locus approximately 250 kb proximal to IDUA. As expected, both Idua and D4S115h are located on the proximal portion of mouse Chr 5 near homologs for other loci on human Chr 4p. Comparison of gene order in mice and humans demonstrates, however, that a chromosomal rearrangement within this conserved synteny has occurred since divergence of lineages leading to mice and humans.
This is the first full report on the genetic linkage between Japanese Huntington's disease and the DNA markers D4S10 and D4S43/S127. With use of the HindIII, BglI, and EcoRI polymorphisms detected at ...D4S10, and the combination of all these polymorphisms to give composite haplotypes, nine Japanese Huntington's disease families were found to be informative. Three recombinants for D4S10 were detected in these families, giving a maximum lod score of 1.662 at a theta of 0.10. Similarly, when we used the MspI and PvuII polymorphisms detected by D4S43/S127, five families gave informative results. No recombinant was detected in these families, giving a maximum lod score of 3.348 at a theta of 0.00. These results clearly support the view that the Japanese Huntington's disease gene may be identical with the Western gene, in spite of the lower prevalence rate in Japan.
The CDKN2 gene that encodes the cell cycle regulatory protein cyclin-dependent kinase-4 inhibitor (p16) has recently been mapped to chromosome 9p21. Frequent homozygous deletions of this gene have ...been documented in cell lines derived from different types of tumors, including breast tumors, suggesting that CDKN2 is a tumor suppressor gene involved in a wide variety of human cancers. To determine the frequency of CDKN2 mutations in breast carcinomas, we screened 37 primary tumors and 5 established breast tumor cell lines by single-strand conformation polymorphism analysis. In addition, Southern blot analysis was performed on a set of five primary breast carcinoma samples and five breast tumor cell lines. Two of the five tumor cell lines revealed a homozygous deletion of the CDKN2 gene, but no mutations were observed in any of the primary breast carcinomas. These results suggest that the mutation of the CDKN2 gene may not be a critical genetic change in the formation of primary breast carcinoma.
We have used a full length cDNA clone to determine the chromosomal location of the gene encoding human ornithine aminotransferase (OAT), a mitochondrial matrix enzyme. Southern blot analysis of Sca ...I-digested DNA from 34 human-mouse somatic cell hybrids revealed 11 human fragments. Three fragments mapped to chromosome 10q23-10qter, confirming the previous provisional assignment of the functional gene to this autosome by analysis of OAT expression in somatic cell hybrids (O'Donnell et al. 1985). The remaining eight fragments were assigned to the X chromosome, and regionally assigned to Xp21-Xp11 by use of an X-chromosome mapping panel. These X chromosome sequences could represent pseudogenes, or related members of a multigene family. Two of the X chromosome fragments are alternate alleles of a restriction fragment length polymorphism (RFLP) making this OAT-related locus an excellent genetic marker. The RFLP may now be used to determine any possible relationship between this locus and several X-linked eye defects.
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