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Biomedical subjects

J R Gulcher

Publications and source records attributed to J R Gulcher.

33 records · Page 2Linked to original sources
PubMed1999

A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13.

Pre-eclampsia is a common and serious disease and a major cause of maternal and infant mortality. Antenatal care systems world-wide screen for signs of the disease such as hypertension and proteinuria. Unlike most other human disorders it impacts two individuals, the mother and the child, both of whom can be severely affected. The pathophysiology of the disorder is incompletely understood, but familial clustering of the disease is apparent. Here we report the results of a genome-wide screen of Icelandic families representing 343 affected women. Including those patients with non-proteinuric pre-eclampsia (gestational hypertension), proteinuric pre-eclampsia and eclampsia, we detected a significant locus on 2p13 with a lod score of 4.70 (single point P < 3.49 x 10(-6)). This is the first reported locus for pre-eclampsia meeting the criteria for genome-wide significance.

Chromosome Mapping↗
PubMed1998

The OMgp gene, a second growth suppressor within the NF1 gene.

The Oligodendrocyte-Myelin glycoprotein gene (OMgp) is placed within an intron of the NF1 gene. Neurofibromin, the product of NF1, acts as a RasGAP and suppresses growth; inactivating mutations in NF1 lead to neurofibromatosis type 1. We report that OMgp also has growth suppressive effects and downregulates mitogenic signaling pathways closely related to those influenced by neurofibromin. Overexpression of OMgp alters mitogenic signaling in NIH3T3 fibroblasts. Cells overexpressing OMgp grow more slowly in serum compared to controls and show a partial G1 block upon cell cycle analysis. PDGF is the primary mitogen for fibroblasts in serum. Overexpression of OMgp alters PDGF signaling in fibroblasts which results in a block of mitogenic signaling. PDGF induced activation of c-Src is blocked, as is the induction of c-Myc and c-Fos, while tyrosine phosphorylation of the PDGFbeta receptor, PLCgamma1 and induction of c-Jun are intact. Although a number of genes embedded within other genes have been described, the biological significance of this arrangement remains unknown. We demonstrate here that structurally unrelated products of two such genes may exercise closely related functions. Our data also raise the possibility of a role for OMgp in disorders of cell proliferation such as NF1.

3T3 Cells↗
PubMed1998

Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system.

The oligodendrocyte-myelin glycoprotein (OMgp) is a 110-kDa glycosylphosphatidylinositol-linked protein that was initially identified as a myelin-specific protein but whose precise function remains unknown. In this study, immunohistochemistry, western blots, in situ hybridization, and northern blots were used to determine the distribution of OMgp in the mouse brain. OMgp is present in a concentration detectable on western blots in the brains of newborn mice, and its concentration gradually increases until day 24 of life. OMgp mRNA is also present in amounts detectable on northern blots in the brains of newborn mice, and its concentration gradually increases until day 21 of life, after which the concentration diminishes a little. Most of the OMgp in the mouse brain appears to be expressed in diverse groups of neurons, but it is particularly prominent in large projection neurons such as the pyramidal cells of the hippocampus, the Purkinje cells of the cerebellum, motoneurons in the brainstem, and anterior horn cells of the spinal cord. However, OMgp is not confined to these cells and is expressed in cells in the white matter as well. The OMgp gene is placed within an intron of the neurofibromatosis type I gene and on the opposite strand. This organization raises the possibility that there may be a relationship between the functions of the products of the two genes. In support of this possibility, we show that within the mouse CNS OMgp and neurofibromin are expressed in the same cell types.

Aging↗
PubMed1997

Mapping of a familial essential tremor gene, FET1, to chromosome 3q13.

Essential tremor (ET), the most common movement disorder in humans, appears to be inherited as an autosomal dominant trait in many families. The familial form is called familial essential tremor (FET), which seems similar to sporadic essential tremor. ET is a cause of substantial disability, particularly in the elderly. The prevalence of Parkinson's disease and dystonia may be increased in families with ET, but other movement disorders are seldom encountered in these families. Here we report the results of a genome-wide scan for FET genes in 16 Icelandic families with 75 affected individuals, in whom FET was apparently inherited as a dominant trait. The scan, which was performed with a 10-cM framework map, revealed one locus on chromosome 3q13 to which FET mapped with a genome-wide significance when the data were analysed either parametrically, assuming an autosomal dominant model (lod score = 3.71), or non-parametrically (NPL Z score = 4.70, p < 6.4 x 10(-6).

Chromosome Mapping↗
PubMed1994

Is multiple sclerosis an autoimmune disease?

It is a commonly held view that multiple sclerosis (MS) may be an autoimmune disease. Most neurology texts list MS as an autoimmune disease and most texts on autoimmunity point to MS as a prime example of an autoimmune disease of the CNS. This view has influenced research into the pathogenesis of MS to the extent that most published work on MS is based on the assumption that it is correct, ignoring other possibilities, unless they can be put into an autoimmune context. Furthermore, most attempts at treating MS have been with agents that influence the immune system. Some of these agents, such as cytoxan and cyclosporin, are drugs with serious side-effects. Hence, it can be argued that over the years some MS patients have suffered because of the autoimmune hypothesis, although in the end and even today, other MS patients may benefit from it. This article examines some of the evidence in support of autoimmune hypotheses of the pathogenesis of MS. We believe that this examination shows that it has not been proven that MS is an autoimmune disease although it underscores the possibility that it may be so. Although it is still a reasonable hypothesis that MS is an autoimmune disease, it has yet to be proven and it would constitute a serious error of omission not to examine other possibilities.

Animals↗
PubMed1991

Structure of the human hexabrachion (tenascin) gene.

The structure of the gene encoding human hexabrachion (tenascin) has been determined from overlapping clones isolated from a human genomic bacteriophage library. The genomic inserts were characterized by restriction mapping, Southern blot analysis, PCR, and DNA sequencing. The coding region of the hexabrachion gene spans approximately 80 kilobases of DNA and consists of 27 exons separated by 26 introns. The exon-intron structure supports a hypothesis based on the cDNA sequence that the hexabrachion gene is an assembly of DNA modules that are also found elsewhere in the genome. Single exons may encode a module, a portion of a module, or a group of modules. The 15 type III units similar to those found in fibronectin are each encoded either by a single exon or by two exons interrupted by an intron. All type III units known to be spliced out of the smaller forms of the protein are encoded by one exon. The fibrinogen-like domain of 210 amino acids is encoded by five exons. The 14.5 epidermal growth factor-like repeats are all encoded by a single exon.

Amino Acid Sequence↗
PubMed1991

The complete cDNA sequence of human hexabrachion (Tenascin). A multidomain protein containing unique epidermal growth factor repeats.

Hexabrachion (Tenascin) is a large glycoprotein that appears in extracellular matrices as a disulfide-linked multimer. It is synthesized in an ordered fashion at particular sites during development, is made in large amounts by certain tumors, and is found in restricted tissue locations in the adult. In this report, we describe the sequence of a full length cDNA of human hexabrachion. The encoded protein contains a total of 2203 amino acids and is a linear array of discrete reiterated domains. At the 5' end are encoded hydrophobic residues and 8 flanking cysteines predicted to be responsible for assembly of hexabrachion polypeptides into a radially arranged, six-armed complex. Following this region are 14 1/2 contiguous 31-amino acid epidermal growth factor-like repeats that have a unique structure with respect to the known examples of this type of domain. Immediately adjacent to these repeats lie 15 uninterrupted segments of approximately 90 amino acids which are similar to the Type III units found in fibronectin. At the carboxyl terminus of the protein is a 210-amino acid domain that is similar to fibrinogen. The domain structure of this protein is consistent with the potential for interaction with multiple ligands and for roles in cell adhesion and/or signaling.

Amino Acid Sequence↗
PubMed1990

Chromosomal localization of the human hexabrachion (tenascin) gene and evidence for recent reduplication within the gene.

Using analysis of rodent-human somatic cell hybrids as well as in situ hybridization of hexabrachion cDNA probes to normal human metaphase chromosomes, we have localized the human hexabrachion gene to chromosome 9, bands q32-q34. We also put forward the hypothesis that there has been a recent reduplication of a small segment of the human hexabrachion gene. We support this hypothesis by comparison of codon usage in this segment of the gene to codon usage in the remainder of the gene. This hypothesis is also supported by comparison of the sequence of human hexabrachion to that of the chicken hexabrachion. In addition, the latter comparison shows that the reduplication most likely occurred after the divergence of mammalian and avian species.

Amino Acid Sequence↗
PubMed1990

The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate.

The complete primary structure of the human oligodendrocyte-myelin glycoprotein (OMgp), a glycophospholipid-linked membrane protein of oligodendrocytes and central nervous system myelin, has been determined. The deduced amino acid sequence predicts a polypeptide of 433 amino acids which includes a 17-amino acid leader sequence. OMgp consists of four domains: (a) a short cysteine-rich motif at the NH2 terminus; (b) a series of tandem leucine-rich repeats (LRs) present in several other proteins where they may play roles in adhesion; (c) a serine/threonine-rich region that contains probable attachment sites for O-linked carbohydrates; and (d) a hydrophobic COOH-terminal segment that is likely to be cleaved concomitant with the attachment of lipid during biosynthesis of OMgp. OMgp shares the first three of its four domains with the platelet glycoprotein Ib, which is responsible for the initial adhesion of platelets to the exposed subendothelium during hemostasis. Together with glycoprotein Ib and several other proteins, OMgp belongs to a family of proteins that contain both an NH2-terminal cysteine-rich motif and an adjacent series of LRs. In addition, we report that a subpopulation of OMgp molecules contains the HNK-1 carbohydrate, which has been shown to mediate interactions among cells in the central nervous system.

Amino Acid Sequence↗
PubMed1989

Binding of hexabrachions to heparin and DNA.

Hexabrachions are extracellular proteins expressed in certain tissues and at specific points in development. cDNA sequencing has revealed that they contain a region of repeats that are similar to the type III homology units of fibronectin. The corresponding region of fibronectin contains heparin- and DNA-binding domains. We have compared the heparin and DNA binding of hexabrachion secreted by the human glioblastoma cell line U87MG to that of fibronectin. Both proteins bound to heparin-agarose in low salt (0.05 M NaCl) buffers. Using linear salt gradients, hexabrachion was eluted from heparin prior to fibronectin. The addition of 5 mM CaCl2 decreased the affinity of both proteins for heparin, but it had a greater effect upon the binding of fibronectin. Free heparin but not chondroitin sulfate inhibited the binding of both proteins to heparin-agarose. In addition, hexabrachion bound to DNA as fibronectin does, and this binding could be inhibited by heparin but not by chondroitin sulfate. Unlike fibronectin, hexabrachion did not bind to gelatin when samples containing both proteins were passed over gelatin-agarose, also indicating that there was no interaction between hexabrachion and fibronectin. In contrast to hexabrachion isolated from brain, the protein secreted by the human glioblastoma cell line U87MG does not bear the HNK-1 epitope which is on a carbohydrate that can mediate interactions between cells.

Calcium↗
PubMed1989

An alternatively spliced region of the human hexabrachion contains a repeat of potential N-glycosylation sites.

We have cloned and sequenced two cDNA molecules that code for parts of two forms of human hexabrachion. The smaller clone has a sequence that corresponds to the previously published sequence of a cDNA clone coding for a part of chicken hexabrachion [Jones, F. S., Burgoon, M. P., Hoffman, S., Crossin, K. L., Cunningham, B. A. & Edelman, G. M. (1988) Proc. Natl. Acad. Sci. USA 85, 2186-2190]. It has eight consecutive domains similar to the type III homology units from fibronectin, several epidermal growth factor repeats, and a domain similar to the beta and gamma chains of fibrinogen. The larger clone has 5' and 3' ends that are identical to the smaller clone but also has an alternatively spliced 1.9-kilobase internal segment. The unique segment contains remarkable repeats of potential glycosylation sites and an additional seven type III homology units.

Amino Acid Sequence↗
PubMed1986

Two large glycosylated polypeptides found in myelinating oligodendrocytes but not in myelin.

Previous work has shown that high molecular weight polypeptides sharing epitopes with myelin-associated glycoprotein are transiently expressed in developing human central nervous system. We describe here the isolation of two of these polypeptides (150 and 225 kDa), their biochemical characterization, and their immunochemical localization. They are both glycosylated and 15 kDa of the apparent molecular mass of both polypeptides is contributed by N-linked carbohydrate moiety(ies). Both have multimeric forms held together by disulfide bonds. Immunochemical and immunohistochemical studies failed to show these polypeptides in myelin. However, in developing human central nervous system, one or both of them are present in the perikaryal cytoplasm and processes of cells with morphology consistent with actively myelinating oligodendrocytes.

Adult↗