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Research

Marked Defects in the Expression and Glycosylation of ₂-HS Glycoprotein/Fetuin-A in Plasma from Neonates with Intrauterine Growth Restriction

Proteomics Screening and Potential Clinical Implications^*

Panagiotis M. Karamessinis^,, Ariadne Malamitsi-Puchner^¶, Theodora Boutsikou^¶, Manousos Makridakis, Konstantinos Vougas, Michael Fountoulakis^||, Antonia Vlahou and George Chrousos^,**,

From the Division of Biotechnology and Section of Endocrinology and Metabolism, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece, ^¶ Neonatal Division, Second Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, 115 28 Athens, Greece, ^|| Center for Medical Genomics, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland, and ^** First Department of Pediatrics, Athens University, Aghia Sophia Childrens Hospital, 11527 Athens, Greece

Intrauterine growth restriction (IUGR) has been associated with increased perinatal morbidity and mortality and increased morbidity and metabolic abnormalities later in life. IUGR is characterized as the failure of a fetus to achieve his or her genetic growth potential in utero. Altered protein expression profiles associated with IUGR may be informative on the pathologic mechanisms of this condition and might reveal potential markers for postnatal complications. The aim of this study was to compare protein profiles of umbilical cord plasma from IUGR and appropriate for gestational age full-term neonates. Blood samples from doubly clamped umbilical cord at delivery from 10 IUGR and 10 appropriate for gestational age full-term neonates were analyzed by two-dimensional electrophoresis and MS. Prominent changes of the ₂-HS glycoprotein/fetuin-A were observed in IUGR cases. Specifically we showed that these changes occur primarily at the level of post-translational modifications of the protein. Using a combination of mass spectrometry and classical biochemical assays, single and heavy chain forms of fetuin-A were found to lack the normally present O-linked sialic acids in IUGR neonates. Fetuin A is a glycoprotein that has been associated with promotion of in vitro cell replication, fetal growth and osteogenesis, and protection from Gram-negative bacterial endotoxins. Prominent defects in glycosylation/sialylation of fetuin-A revealed by our study might be responsible for impaired function of fetuin-A, leading to deficient fetal growth, especially osteogenesis, and/or to the development of complications frequently seen later in the lives of IUGR neonates.

To whom correspondence may be addressed: First Dept. of Pediatrics, University of Athens, Aghia Sophia Childrens Hospital, Thivon & Papadiamantopoulou, 11527 Athens, Greece. Tel.: 302107794023; Fax: 302107759167; E-mail: chrousge{at}med.uoa.gr