title: Abnormal Proteoglycan Synthesis Due to Gene Defects Causes Skeletal Diseases with Overlapping Phenotypes.
abstract: In recent years, massively parallel sequencing technologies have helped us to identify novel disease genes and solve the mysteries behind rare diseases. Today, we know that some diseases with many overlapping and distinct clinical features, as presented in this review, can be caused by mutations in genes that encode enzymes playing crucial roles at different steps of the exact same pathway. In this review, we exclusively focused on 5 genes -XYLT1,XYLT2,B4GALT7,B3GALT6, andB3GAT3- that encode enzymes involved in the biosynthesis of the common tetrasaccharide linker region of proteoglycans and review the associated diseases, also referred to as linkeropathies, by summarizing the cases reported in literature. Since proteoglycans are essential macromolecules in development, signaling and homeostasis of many tissues and organs, mutations in these genes can affect many organs; including bone, cartilage, eyes, ears, heart, and skin. Short stature, developmental delay, facial dysmorphism, and skeletal dysplasias are some of the common features observed in patients with mutations in these genes. Among these genes,XYLT2mutations cause a relatively distinct phenotype, the so-called spondyloocular syndrome, which is characterized by clinical presentation of a very severe childhood-onset primary osteoporosis, cataract, and hearing impairment. The full phenotype spectrum of diseases mentioned here is likely to expand with additional clinical reports and further molecular studies.
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Taylan
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Mäkitie
mesh_terms: D001847:Bone Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005700:Galactosyltransferases / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010430:Pentosyltransferases / Q000235:genetics; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism*; D000097608:UDP Xylose-Protein Xylosyltransferase
chemical_list: D005700:Galactosyltransferases; D014453:Glucuronosyltransferase; D010430:Pentosyltransferases; D011509:Proteoglycans; D000097608:UDP Xylose-Protein Xylosyltransferase; C425302:B3GALT6 protein, human; C063053:xylosylprotein 4-beta-galactosyltransferase; C000594393:B3GAT3 protein, human