PubMed Health⌕ Search

Biomedical subjects

T C Gilliam

Publications and source records attributed to T C Gilliam.

15 recordsLinked to original sources
PubMed1992

Mapping psychiatric disease genes: impact of new molecular strategies.

Genetic mapping of genes which predispose to psychiatric illness is discussed in relation to recent developments in molecular genetic technology. Among the psychiatric disorders, the mechanism by which genetic factors contribute to illness is poorly understood, and the classification of phenotype (ill-status) is extremely complicated. These uncertainties, together with other complicating factors, tend to undermine the effectiveness of genetic linkage analysis. Two very powerful new molecular strategies have the potential to improve the overall gene mapping effort. First, new applications of polymerase chain reaction (PCR) technology will allow laboratories to generate much more genetic data than has been previously possible. Some of the factors which confound psychiatric linkage analysis should be mitigated by the larger data sets that will be generated with this technology. Second, the cloning of large segments of human chromosomes into yeast artificial chromosomes (YACs) has given rise to strategies to clone and catalog the entire human genome. The goal of constructing overlapping YAC clones (contigs) end-to-end across each human chromosome now appears imminent. This development will have immense effect upon our ability to identify disease genes.

Chromosome Mapping↗
PubMed1992

Isolation and characterization of a highly polymorphic human locus (DXS455) in proximal Xq28.

Human Xq28 is highly gene dense with over 27 loci. Because most of these genes have been mapped by linkage to polymorphic loci, only one of which (DXS52) is informative in most families, a search was conducted for new, highly polymorphic Xq28 markers. From a cosmid library constructed using a somatic cell hybrid containing human Xq27.3----qter as the sole human DNA, a human-insert cosmid (c346) was identified and found to reveal variation on Southern blot analyses with female DNA digested with any of several different restriction endonucleases. Two subclones of c346, p346.8 and p346.T, that respectively identify a multiallelic VNTR locus and a frequent two-allele TaqI polymorphism were isolated. Examination of 21 unrelated females showed heterozygosity of 76 and 57%, respectively. These two markers appeared to be in linkage equilibrium, and a combined analysis revealed heterozygosity in 91% of unrelated females. Families segregating the fragile X syndrome with key Xq28 crossovers position this locus (designated DXS455) between the proximal Xq28 locus DXS296 (VK21) and the more distal locus DXS374 (1A1), which is proximal to DXS52. DXS455 is therefore the most polymorphic locus identified in Xq28 and will be useful in the genetic analysis of this gene dense region, including the diagnosis of nearby genetic disease loci by linkage.

Alleles↗
PubMed1992

Identification and localization of microsatellite markers covering human chromosome 18.

To generate microsatellite markers from chromosome 18, we have cytogenetically localized a large number of lambda phage using a deletion mapping panel of somatic cell hybrids. Here we describe the identification of 65 new CA-repeat-containing phage and the localization of five markers developed in other laboratories. This approach allows the selection of a subset of markers that are well spaced across the chromosome and can be developed as genetic markers. The use of PCR-based markers should allow for the rapid genomic screening of disease genes on chromosome 18.

Base Sequence↗
PubMed1992

Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q.

Autosomal recessive Duchenne-like muscular dystrophy (DLMD) is a severe dystrophic myopathy. The incidence is unknown because of its clinical similarity to Duchenne muscular dystrophy (DMD). Three highly inbred DLMD families from Tunisia were analysed for chromosomal linkage using 135 polymorphic microsatellite markers. A significant lod score of z = 9.15 at theta = 0.03 was found with the 13q12 locus D13S115. Two additional 13q12 markers, D13S143 and D13S120, also gave significant lod scores. Therefore, the primary DLMD defect gene lies in the pericentrometric region of chromosome 13q.

Centromere↗
PubMed1991

Mapping of human microtubule-associated protein 1B in proximity to the spinal muscular atrophy locus at 5q13.

A polyclonal antiserum directed against the C-terminal domain of dystrophin was used to isolate a cDNA clone encoding an antigenically cross-reactive protein, microtubule-associated protein 1B (MAP-1B). Physical mapping of the human MAP-1B locus places its chromosomal location at 5q13, in proximity to the spinal muscular atrophy (SMA) locus. SMA is a degenerative disorder primarily affecting motor neurons. Genetic linkage analysis of SMA families using a human dinucleotide repeat polymorphism just 3' of the MAP-1B gene has shown tight linkage to SMA mutations. These mapping data together with the postulated role of MAP-1B in neuronal morphogenesis and its localization in anterior horn motor neurons suggest a possible association with SMA.

Animals↗
PubMed1991

Genetic mapping of "Lubag" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome.

"Lubag" is an X-linked disorder causing dystonia and parkinsonism that has only been described in families from the Philippines, principally from the island of Panay. We have established linkage between the disease phenotype "lubag" and DNA markers which span the Xp11.22-Xq21.3 region by using a large Filipino family with 8 affected men in three generations. These DNA markers define an interval of about 20 centimorgans in the pericentromeric region of the X chromosome as the most likely site of the disease locus XDPD (X-linked dystonia-parkinsonism). XDPD has a maximum multipoint log likelihood ratio score (Zmax) of about 4.6 over the interval from Xq12 to Xq21.31 (DXS159-DXYS1X). The co-occurrence of dystonia and parkinsonism in lubag and in other known disorders suggests there may be a common pathogenetic mechanism. Identification of the genetic defect in this family may provide an important clue toward understanding the pathogenesis and pathophysiology of both dystonia and parkinsonism.

Adult↗
PubMed1991

Spinal muscular atrophy is not the result of mutations at the beta-hexosaminidase or GM2-activator locus.

The disease locus for the clinically heterogeneous childhood spinal muscular atrophies (SMA) maps to the chromosome 5 subregion, 5q11.2-13.3. The beta-subunit of beta-D-N-acetylhexosaminidase (hexosaminidase) (EC 3.2.1.52) (Hex B) maps to the same region, and the protein required for substrate recognition by this enzyme, GM2-activator protein, likewise maps to chromosome 5. We have investigated the possibility of allelic variation among some forms of SMA and hexosaminidase deficiency. Recombination between the Hex B and SMA loci eliminates this enzyme as a candidate site for defects causing the illness. Furthermore, we show that, despite previous evidence to the contrary, the GM2-activator locus does not map to chromosome 5, thereby eliminating it as a candidate gene for SMA.

Amino Acid Sequence↗
PubMed1990

Genetic homogeneity between acute and chronic forms of spinal muscular atrophy.

The childhood-onset spinal muscular atrophies (SMAs) describe a heterogeneous group of disorders that selectively affect the alpha motoneuron. We have shown that chronic childhood-onset SMA (SMA II and III) maps to a single locus on chromosome 5q. Acute SMA (SMA Type I/Werdnig-Hoffmann/severe/infantile) is the main cause of heritable infant mortality. Mapping the acute SMA locus by conventional methods is complicated by the rapidly fatal course of the disease and its recessive mode of inheritance. We present here the typing of four inbred acute-SMA families with DNA markers on chromosome 5q and analysis of these together with acute families from our previous study to demonstrate genetic homogeneity between the acute and chronic forms of SMA. The data indicate that the acute SMA locus maps to chromosome 5q11.2-13.3. Two families seem unlinked to 5q markers, raising the possibility of genetic heterogeneity or disease misclassification within the acute and chronic family sets.

Acute Disease↗
PubMed1990

Report of a workshop on genetic linkage studies in schizophrenia.

A workshop on genetic linkage studies in schizophrenia was held at Columbia University's Arden House Conference Center in October 1989. This report summarizes the contents of invited talks by Drs. Arno Motulsky and T. Conrad Gilliam and the discussions at the five workshop sessions. Topics of the workshop sessions were (1) diagnostic boundaries and hierarchies in schizophrenia, (2) genetic models and linkage parameters, (3) selection and ascertainment of pedigrees, (4) future extensions of molecular genetics strategies, and (5) possibilities for future collaboration.

Genetic Linkage↗
PubMed1989

Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia.

Two independent lines of evidence support the localization of a schizophrenia susceptibility locus to the proximal long arm of chromosome 5. A partial trisomy of chromosome 5 (5q11.2-q13.3) cosegregates with the disorder in a Canadian family of Chinese descent, and DNA markers from proximal 5q cosegregate with schizophrenia (plus related disorders) in families of British and Icelandic descent. We constructed a human:hamster hybrid cell line (HHW 1064) whose only human complement is a chromosome 5 that is missing the trisomic region associated with schizophrenia. In combination with a "matched" cell hybrid (HHW 105) containing an intact chromosome 5, we physically mapped DNA markers relative to the trisomy. "Schizophrenia-linked" DNA markers p105-153Ra (D5S39) and p105-599Ha (D5S76) map within the trisomy and proximal to the 5q11.2 breakpoint, respectively. The hybrid cell lines HHW 105 and HHW 1064 together provide a means to identify and generate syntenic DNA markers to further investigate the location of a schizophrenia locus.

Animals↗