heparitin-sulfate and Growth-Disorders

Topics: Animals; Body Patterning; Cell Membrane; Drosophila Proteins; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Membrane Glycoproteins; Models, Molecular; Molecular Structure; Polysaccharides; Proteoglycans; Signal Transduction; Syndrome

Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

Topics: Abnormalities, Multiple; Animals; Beckwith-Wiedemann Syndrome; Body Weight; Cell Division; Female; Genotype; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Insulin-Like Growth Factor II; Kidney Tubules, Collecting; Male; Mandible; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Phenotype; Proteoglycans; Syndrome

Simpson-Golabi-Behmel syndrome (SGBS) is one of the overgrowth syndromes. Microdeletions of the glypican-3 (GPC3) gene were described by Pilia et al. (1996). Glypican-3 encodes a putative extracellular proteoglycan which is expressed in embryonic mesodermal tissues and plays an important role in embryonal growth. We report a Japanese patient with SGBS who had a single base deletion in the exon 7 of the GPC3 gene. This is the first report of a single base deletion of the GPC3 gene.

Topics: Abnormalities, Multiple; Amino Acid Sequence; Base Sequence; Exons; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Hernia, Diaphragmatic; Humans; Infant, Newborn; Male; Proteoglycans; Radiography; Sequence Deletion; Syndrome

Simpson-Golabi-Behmel Syndrome (SGBS) is an X-linked disease characterized by pre- and postnatal overgrowth. Recently, we have shown that mutations in the glypican family gene, GPC3, cause SGBS. This gene is predominantly expressed in the same mesoderm-derived tissues that overgrow in its absence. To investigate the basis for promoter function, 3.3kb of GC-rich DNA 5' of the transcribed region were fused to a luciferase cDNA, transfected into Caco-2 and NT2 cells, and assayed for activity. Deletion analysis identified a 218-bp fragment upstream of the transcription start site that conferred more than 80% of maximal reporter gene activation. This fragment contains five putative Sp1 binding sites, three of which (centered at nt -14, -34, and -92) were active when assessed by DNaseI footprinting and gel shift/supershift assays. Additionally, Sp1 specifically transactivated transcription in Sp1-deficient Drosophila SL2 cells, demonstrating the functionality of Sp1 on the GPC3 promoter. A full-length promoter construct was also highly active in HeLa cells, which do not express endogenous GPC3. These results indicate that the GPC3 promoter is dependent on Sp1 for proper activation, but tissue-specific repression in non-expressing cells must involve either DNA that lies outside the region tested or auxiliary structural features of chromatin.

Topics: Animals; Base Sequence; Binding Sites; Caco-2 Cells; Cell Line; DNA; Drosophila; Gene Expression Regulation; Glypicans; Growth Disorders; HeLa Cells; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Molecular Sequence Data; Mutation; Oligonucleotide Probes; Promoter Regions, Genetic; Proteoglycans; Sp1 Transcription Factor; Syndrome; Transcriptional Activation

Topics: Animals; Chromosome Mapping; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; In Situ Hybridization, Fluorescence; Proteoglycans; Rats; Syndrome; X Chromosome

To identify the proportion and type of deletions present in the glypican 3 (GPC3) gene in a group of patients with Simpson-Golabi-Behmel syndrome (SGBS).. PCR analysis using primer pairs which amplify fragments from each of the eight exons of the GPC3 gene was carried out in a series of 18 families with SGBS (approximately half of reported cases).. Deletions were detected in only five families (one reported previously). We found deletions in all exons of the gene except exon 3.. Our results suggest that large scale deletions may be less common in SGBS than was originally thought. One patient, with an exon 4 and 5 deletion, lacked the characteristic facial dysmorphic features. This raises the possibility of involvement of GPC3 gene defects in a wider range of overgrowth disorders.

Topics: Abnormalities, Multiple; Child; Exons; Face; Genetic Linkage; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Male; Phenotype; Polymerase Chain Reaction; Proteoglycans; Sequence Deletion; Syndrome; X Chromosome

We present the case of a male infant, born prematurely (at 33 weeks gestation) with macrosomia, disproportionate macrocephaly, facial dysmorphism, short penis and a small umbilical defect. He had a large ASD and was ventilated from birth for respiratory distress syndrome. He died at 12 hours of age despite neonatal ITU care. Post-mortem examination showed highly lobulated kidneys with nodules of blastema and foci of hamartomatous change in the medulla. Prominence of pancreatic islet cells and expansion of hepatic portal tracts were also noted. His mother has minor cervical spine abnormalities. We discuss the differential diagnosis and the difficulty in confidently assigning a diagnosis to this patient, as considerable overlap is becoming evident between Simpson-Golabi-Behmel syndrome and Perlman syndrome.

Topics: Abnormalities, Multiple; Beckwith-Wiedemann Syndrome; Chromosomes, Human, Pair 11; Face; Female; Glypicans; Growth Disorders; Heart Septal Defects, Atrial; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Infant, Newborn; Kidney; Liver; Male; Pancreas; Pregnancy; Proteoglycans; Syndrome

Topics: Abnormalities, Multiple; Animals; Beckwith-Wiedemann Syndrome; Gigantism; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Insulin-Like Growth Factor II; Proteoglycans; Receptor, IGF Type 2; Syndrome

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre- and postnatal overgrowth with visceral and skeletal anomalies. To identify the causative gene, breakpoints in two female patients with X;autosome translocations were identified. The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS. GPC3 encodes a putative extracellular proteoglycan, glypican 3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed. Initial western- and ligand-blotting experiments suggest that glypican 3 forms a complex with insulin-like growth factor 2 (IGF2), and might thereby modulate IGF2 action.

Topics: Abnormalities, Multiple; Amino Acid Sequence; Animals; Base Sequence; Cell Line; Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 16; Cloning, Molecular; DNA Primers; Female; Gene Deletion; Genetic Linkage; Glypicans; Growth Disorders; HeLa Cells; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunologic Techniques; Insulin-Like Growth Factor II; Male; Mice; Molecular Sequence Data; Pedigree; Protein Binding; Proteoglycans; Sequence Homology, Amino Acid; Syndrome; Translocation, Genetic; Tumor Cells, Cultured; X Chromosome