heparitin-sulfate and Immunologic-Deficiency-Syndromes

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type

Topics: Animals; Bone Diseases, Developmental; Child, Preschool; Developmental Disabilities; Female; Heparitin Sulfate; Humans; Immunologic Deficiency Syndromes; Induced Pluripotent Stem Cells; Infant; Lymphocytes; Mutation; N-Acetylglucosaminyltransferases; Zebrafish

The role proteoglycans play in tumor formation was examined by measuring the tumorigenicity of proteoglycan-deficient Chinese hamster ovary cell mutants in nude mice. When 10(7) cells were injected subcutaneously, mutants with less than about 15% of the wild-type level of proteoglycan synthesis did not produce tumors. Mutants defective in the synthesis of heparan sulfate proteoglycans also did not form tumors, whereas mutants with altered chondroitin sulfate proteoglycans were tumorigenic. Tumors arose from mixtures of wild-type and nontumorigenic mutant cells and contained both cell types, suggesting that wild-type cell proteoglycans enabled mutant cells to survive. The failure of heparan sulfate-deficient mutants to form tumors depended on the ability of the host to mount a B cell-mediated immune reaction.

Topics: Animals; B-Lymphocytes; Cell Line; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Cricetinae; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Immunologic Deficiency Syndromes; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Neoplasm Transplantation; Neoplasms, Experimental; Pentosyltransferases; Proteoglycans; UDP Xylose-Protein Xylosyltransferase