The Skeletal Manifestations of Deranged Glycosylation

The congenital disorders of glycosylation (CDG) are a rapidly expanding disease group with protean presentations in which the skeletal manifestations are often not appreciated. In this brief review we will discuss the skeletal manifestation of CDG patients, their potential clinical and functional impact on the CDG child and their family, and consider possible underlying mechanisms of these skeletal manifestations. Molecular and functional insights into clinical disease phenotypes associated with a primary skeletal dysplasia phenotype eg. achondrogenesis type 1A, provides invaluable, mechanistic understanding to pathology in defects associated with primary and secondary glycan deficiencies. *Corresponding author: David Coman, Associate Professor, Department of Metabolic Medicine, The Royal Children’s Hospital, Herston Road, Herston 4029, Brisbane, Australia, Tel: +61736368111; E-mail: [email protected] Received November 25, 2011; Accepted December 19, 2011; Published January 05, 2012 Citation: Coman D, Savarirayan R (2012) The Skeletal Manifestations of Deranged Glycosylation. Pediatr Therapeut S3:002. doi:10.4172/2161-0665.S3-002 Copyright: © 2012 Coman D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Glycosylation is a ubiquitous post translational modification (PTM) of proteins and lipids, with an estimated 1% of the human genome dedicated to the process [1]. In eukaryotes the linkage of glycans to proteins and lipids is carried out by eleven biosynthetic pathways [2]. The covalent attachment of a glycan onto a protein constitutes the glycosylation process, an important PTM involved in folding, stability and interactions of glycoproteins. In eukaryotes the linkage of glycans to proteins and lipids is carried out by eleven biosynthetic pathways [1], six of which are associated with human genetic disorders. The last decade has seen a rapid delineation of genetic glycosylation disorders which have been identified predominantly in the individual N-linked and O-linked protein glycosylation pathways (16 and 8 diseases respectively), while combined defects in both the Nand the O-glycosylation pathways, or other pathways eg O-Mannosylation have also been described (17 diseases). These genetic defects in PTM have multi-system clinical manifestations with the central nervous system being a consistent site for disease morbidity for the CDG child and their family. The transfer of initial sugar(s) to glycoproteins or glycolipids occurs in the endoplasmic reticulum (ER) or on the ER membrane. The subsequent addition of the many different sugars that make up a mature glycan is accomplished in the Golgi. Golgi membranes are embedded with glycosidases, glycosyltransferases, and nucleotide sugar transporters from the cis-Golgi to the trans-Golgi network (TGN). N-glycosylation starts primarily in the ER while O-glycosylation occurs in the Golgi. Recently primary genetic defects within the Golgi network have been described in humans and animal models in whom a primary skeletal dysplasia phenotype has been the presenting feature, and even a lethal manifestation in some cases eg achondrogenesis type 1A (OMIM 200600). Hypochondroplasia (OMIM 146000) is a common skeletal dysplasia due to mutations in the Fibroblast Growth Factor Receptor 3 gene (FGFR3). Novel mutations in FGFR3 disrupt a putative Nglycosylation site and where the phenotype most probably results from altered receptor glycosylation [3]. Understanding the pathogenesis of defects in these cellular compartments is relevant to understanding the embryogeneic defects observed in children with CDG and potentially in creating targets treatment options. While the clinical features observed in CDG are protean, those that incur the highest disease burden involve the central nervous system, gastrointestinal and cardiac disease systems [4].A previous review reported the wide spectrum of skeletal phenotypes reported in CDG [5] which are summarised in table 1. In this review we discuss the skeletal manifestations of CDG, postulate as to their mechanism, and draw correlations from an evolving body of evidence from the primary skeletal dysplasia’s. Skeletal manifestations of the congenital disorders of glycosylation The most common CDG is secondary to Phosphomannomutase 2 deficiency (PMM2) PMM2-CDG (CDG-Ia) (OMIM212065) [6]. The most commonly reported skeletal manifestations of CDG-Ia are those of osteopenia, thoracic cage abnormalities, short stature, kyphosis and scoliosis. Less common manifestations include a “dysostosis multiplex like phenotype”, a “bone-in-bone” appearance, C1-C2 subluxation and platyspondyly, a primary skeletal dysplasia reminiscent of a type II collagenopathy [7-10]. Some of the observed defects may be multifactorial in aetiology eg. joint contractures and camptodactyly may be secondarily observed peripheral features as a consequence of central nervous system dysfunction. Table 1 summarise the more commonly reported skeletal manifestations in CDG patients, and a more comprehensive review of the delineated skeletal features are summarised in [5] Peters Plus syndrome (OMIM 261540) is an autosomal recessive disorder with the main clinical features involving anterior eye-chamber defects, short stature, developmental delay and cleft lip/palate [11]. It is caused by mutations in beta-1,3-galactosyltransferase-like gene (B3GALTL) which encodes a β1,3-glucosyltransferase [11], which as Citation: Coman D, Savarirayan R (2012) The Skeletal Manifestations of Deranged Glycosylation. Pediatr Therapeut S3:002. doi:10.4172/2161-0665. S3-002