OBJECTIVE: The function of IGF system components is affected by their glycosylation status in vitro. However, little is known about the role of glycosylation status of these components in vivo. In this study we determined the impact of glycosylation on the endocrine IGF system in children with the rare syndrome of congenital disorders of glycosylation (CDG). DESIGN: Analyses of serum samples from children with CDG and healthy controls. PATIENTS: Children with CDG (N = 12) were recruited as part of a separate clinical study of mannose therapy at the Mayo Clinic. Serum from control children (N = 11) were obtained as routine samples before discard. MEASUREMENTS: Levels and glycosylation state of components of the IGF system and ability to form physiologically relevant ternary complexes composed of IGF, IGFBP-3, and an acid-labile subunit (ALS). RESULTS: Serum levels of IGF-1, IGF-2, ALS, and IGFBP-3 were reduced (P < 0.05) in children with CDG when compared to controls. Immunoblot analysis showed incomplete glycosylation of ALS and IGFBP-3 and impaired ternary complex formation in CDG. Partial normalization of ALS and IGFBP-3 glycosylation was associated with improvement in linear growth in a child with CDG-Ib during initiation of oral mannose therapy. CONCLUSIONS: Inadequate glycosylation of IGFBP-3 and ALS has a negative effect on the function of these proteins in vivo. This study provides the first evidence in humans for the importance of glycosylation on components of the IGF system.
OBJECTIVE: The function of IGF system components is affected by their glycosylation status in vitro. However, little is known about the role of glycosylation status of these components in vivo. In this study we determined the impact of glycosylation on the endocrine IGF system in children with the rare syndrome of congenital disorders of glycosylation (CDG). DESIGN: Analyses of serum samples from children with CDG and healthy controls. PATIENTS: Children with CDG (N = 12) were recruited as part of a separate clinical study of mannose therapy at the Mayo Clinic. Serum from control children (N = 11) were obtained as routine samples before discard. MEASUREMENTS: Levels and glycosylation state of components of the IGF system and ability to form physiologically relevant ternary complexes composed of IGF, IGFBP-3, and an acid-labile subunit (ALS). RESULTS: Serum levels of IGF-1, IGF-2, ALS, and IGFBP-3 were reduced (P < 0.05) in children with CDG when compared to controls. Immunoblot analysis showed incomplete glycosylation of ALS and IGFBP-3 and impaired ternary complex formation in CDG. Partial normalization of ALS and IGFBP-3 glycosylation was associated with improvement in linear growth in a child with CDG-Ib during initiation of oral mannose therapy. CONCLUSIONS: Inadequate glycosylation of IGFBP-3 and ALS has a negative effect on the function of these proteins in vivo. This study provides the first evidence in humans for the importance of glycosylation on components of the IGF system.
Authors: Laura C Tegtmeyer; Stephan Rust; Monique van Scherpenzeel; Bobby G Ng; Marie-Estelle Losfeld; Sharita Timal; Kimiyo Raymond; Ping He; Mie Ichikawa; Joris Veltman; Karin Huijben; Yoon S Shin; Vandana Sharma; Maciej Adamowicz; Martin Lammens; Janine Reunert; Anika Witten; Esther Schrapers; Gert Matthijs; Jaak Jaeken; Daisy Rymen; Tanya Stojkovic; Pascal Laforêt; François Petit; Olivier Aumaître; Elzbieta Czarnowska; Monique Piraud; Teodor Podskarbi; Charles A Stanley; Reuben Matalon; Patricie Burda; Soraya Seyyedi; Volker Debus; Piotr Socha; Jolanta Sykut-Cegielska; Francjan van Spronsen; Linda de Meirleir; Pietro Vajro; Terry DeClue; Can Ficicioglu; Yoshinao Wada; Ron A Wevers; Dieter Vanderschaeghe; Nico Callewaert; Ralph Fingerhut; Emile van Schaftingen; Hudson H Freeze; Eva Morava; Dirk J Lefeber; Thorsten Marquardt Journal: N Engl J Med Date: 2014-02-06 Impact factor: 91.245
Authors: Jaime Chu; Alexander Mir; Ningguo Gao; Sabrina Rosa; Christopher Monson; Vandana Sharma; Richard Steet; Hudson H Freeze; Mark A Lehrman; Kirsten C Sadler Journal: Dis Model Mech Date: 2012-08-16 Impact factor: 5.758