heparitin-sulfate and Heart-Defects--Congenital

Diverse cardiac abnormalities have been reported in patients with the Simpson-Golabi-Behmel syndrome (SGBS), and it is suspected that they are related to the apparently high incidence of early death. To clarify the incidence and significance of the various cardiac abnormalities, we reviewed 101 SGBS patients (89 from the literature, 12 new). All were male, except for one clearly affected female patient with translocation X;1 [Punnett, 1994: Am J Med Genet 50: 391-393]. Ninety-six of 99 (97%) patients had the classic phenotype of macrosomia and typical "coarse" face. Thirty-six patients (36%) had a cardiac abnormality, of whom 26 (26%) had a cardiovascular malformation (CVM). After excluding 24 patients with insufficient clinical data, these percentages among the 77 informative cases were 47% and 34%, respectively. When grouped according to a mechanistic classification, most cases (20/ 26, or 77%) were class II CVMs (attributed to altered embryonic intracardiac flow). Other cardiac abnormalities included cardiomyopathy (n = 4) and electrocardiogram (ECG) conduction or rhythm abnormalities (n = 12); three of the affected patients (25%) also had a CVM. Among 92 informative cases, there were 29 (32%) deaths, a figure that excludes seven elective terminations. Among the 25 patients younger than 3 years, death was associated with a cardiac abnormality in six (23%). GPC3 mutation analysis using Southern blot testing and polymerase chain reaction amplification was performed for 37 of 101 (37%) patients. A mutation was detected in 26 of the 37 patients tested (70%), 12 of whom (46%) had a cardiac abnormality. We conclude that cardiac abnormalities of any type are common in SGBS (almost one-half of informative cases), with CVMs seen in one-third of cases. The heterogeneous ECG abnormalities in this survey must be viewed with caution, since they may represent a genuine component of the syndrome or reporting bias. Determining the true prevalence and natural history of cardiac abnormalities in SGBS will require a larger number of patients and more consistent prospective cardiac evaluations. There are sufficient data to recommend a baseline echocardiogram and ECG in SGBS patients. Data are insufficient to define a cardiac phenotype/molecular correlation.

Topics: Adolescent; Adult; Child; Child, Preschool; DNA Mutational Analysis; Female; Fetal Death; Glypicans; Heart Defects, Congenital; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Infant; Male; Mutation; Proteoglycans; Syndrome

Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.

Topics: Abnormalities, Multiple; Arrhythmias, Cardiac; Genetic Diseases, X-Linked; Gigantism; Glypicans; Heart Defects, Congenital; Hedgehog Proteins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Intellectual Disability; Signal Transduction

Impaired heparan sulfate (HS) synthesis in vertebrate development causes complex malformations due to the functional disruption of multiple HS-binding growth factors and morphogens. Here, we report developmental heart defects in mice bearing a targeted disruption of the HS-generating enzyme GlcNAc N-deacetylase/GlcN N-sulfotransferase 1 (NDST1), including ventricular septal defects (VSD), persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), and retroesophageal right subclavian artery (RERSC). These defects closely resemble cardiac anomalies observed in mice made deficient in the cardiogenic regulator fibroblast growth factor 8 (FGF8). Consistent with this, we show that HS-dependent FGF8/FGF-receptor2C assembly and FGF8-dependent ERK-phosphorylation are strongly reduced in NDST1(-/-) embryonic cells and tissues. Moreover, WNT1-Cre/LoxP-mediated conditional targeting of NDST function in neural crest cells (NCCs) revealed that their impaired HS-dependent development contributes strongly to the observed cardiac defects. These findings raise the possibility that defects in HS biosynthesis may contribute to congenital heart defects in humans that represent the most common type of birth defect.

Topics: Animals; DNA Primers; Double Outlet Right Ventricle; Fibroblast Growth Factor 8; Heart; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Heparitin Sulfate; Immunohistochemistry; Mice; Mice, Knockout; Neural Crest; Organogenesis; Reverse Transcriptase Polymerase Chain Reaction; Subclavian Artery; Sulfotransferases; Truncus Arteriosus, Persistent

Heparin-induced thrombocytopenia is a rare and serious complication of anticoagulation therapy. There remains a paucity of information pertaining to alternative anticoagulation strategies for use during cardiopulmonary bypass concomitant with heparin-induced thrombocytopenia, especially in children. We report the successful treatment of heparin-induced thrombocytopenia and subsequent hemorrhagic complications postoperatively in a 2-year-old child with Danaparoid (orgaran). Emergent conduit revision with cardiopulmonary bypass was required for a thrombosed systemic-venous to pulmonary-arterial connection (completion modified Fontan procedure). Required doses of Danaparoid were consistently twofold that previously reported for adults.

Topics: Anticoagulants; Cardiopulmonary Bypass; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heart Defects, Congenital; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombosis

Perlecan is a heparan sulfate proteoglycan that is expressed in all basement membranes (BMs), in cartilage, and several other mesenchymal tissues during development. Perlecan binds growth factors and interacts with various extracellular matrix proteins and cell adhesion molecules. Homozygous mice with a null mutation in the perlecan gene exhibit normal formation of BMs. However, BMs deteriorate in regions with increased mechanical stress such as the contracting myocardium and the expanding brain vesicles showing that perlecan is crucial for maintaining BM integrity. As a consequence, small clefts are formed in the cardiac muscle leading to blood leakage into the pericardial cavity and an arrest of heart function. The defects in the BM separating the brain from the adjacent mesenchyme caused invasion of brain tissue into the overlaying ectoderm leading to abnormal expansion of neuroepithelium, neuronal ectopias, and exencephaly. Finally, homozygotes developed a severe defect in cartilage, a tissue that lacks BMs. The chondrodysplasia is characterized by a reduction of the fibrillar collagen network, shortened collagen fibers, and elevated expression of cartilage extracellular matrix genes, suggesting that perlecan protects cartilage extracellular matrix from degradation.

Topics: Animals; Basement Membrane; Calcification, Physiologic; Cartilage; Cells, Cultured; Collagen; Exostoses, Multiple Hereditary; Gene Targeting; Genes, Lethal; Heart Defects, Congenital; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Homozygote; Mice; Mice, Congenic; Mice, Mutant Strains; Mutagenesis, Insertional; Neural Tube Defects; Ossification, Heterotopic; Proteoglycans; Restriction Mapping