Serum bikunin isoforms in congenital disorders of glycosylation and linkeropathies

Abstract

Bikunin (Bkn) isoforms are serum chondroitin sulfate (CS) proteoglycans synthesized by the liver. They include two light forms, that is, the Bkn core protein and the Bkn linked to the CS chain (urinary trypsin inhibitor [UTI]), and two heavy forms, that is, pro-α-trypsin inhibitor and inter-α-trypsin inhibitor, corresponding to UTI esterified by one or two heavy chains glycoproteins, respectively. We previously showed that the Western-blot analysis of the light forms could allow the fast and easy detection of patients with linkeropathy, deficient in enzymes involved in the synthesis of the initial common tetrasaccharide linker of glycosaminoglycans. Here, we analyzed all serum Bkn isoforms in a context of congenital disorders of glycosylation (CDG) and showed very specific abnormal patterns suggesting potential interests for their screening and diagnosis. In particular, genetic deficiencies in V-ATPase

Chondrodysplasias With Multiple Dislocations Caused by Defects in Glycosaminoglycan Synthesis

“…In patient fibroblasts, B4GALT7 mutations result in abnormal biosynthesis of mature decorin and biglycan with reduced GAG chain epimerization (Quentin et al, 1990 ; Seidler et al, 2006 ). Recently, a reduced level of bikunin bearing CS chain was detected by Western blot in patient serum compared with healthy controls (Bruneel et al, 2018 ; Haouari et al, 2020 ). Both knockdown (morphant) and mosaic knockdown b4galt7 zebrafish models presented short stature, deformed pectoral fins, craniofacial dysmorphism, and reduced mineralization (Delbaere et al, 2020 ).…”

“…Fibroblasts from affected individuals exhibited altered GAG synthesis with impaired glycanation of decorin and marked reduction of HS synthesis (Malfait et al, 2013 ; Nakajima et al, 2013 ; Ritelli et al, 2015 ). As for patients with B4GALT7 mutations, a reduced level of bikunin bearing CS chain was detected by Western blot in patient serum compared to healthy controls (Bruneel et al, 2018 ; Haouari et al, 2020 ).…”

“…Patient fibroblasts exhibited reduced CS, DS, and HS and an increased level of DS-free decorin as compared with healthy controls (Baasanjav et al, 2011 ). Moreover, a reduced level of bikunin bearing CS chain was detected in patient serum compared with healthy controls (Bruneel et al, 2018 ; Haouari et al, 2020 ). B3gat3 -deficient mice synthesized a smaller CS and HS chain in their blastocysts than that of heterozygous mice and exhibited an embryonic lethality before the eight-cell stage due to the failure of cytokinesis (Izumikawa et al, 2010 ).…”

“…Reduced N-glycan branching has been evidenced in patient cells and plasma compared with control (Edvardson et al, 2013 ). Moreover, due to its localization and the transporter substrate, it was assumed that SLC35A3 might affect GAG metabolism, and, recently, an abnormal migration profile of bikunin bearing CS chain was observed on Western blot on patient serum (Haouari et al, 2020 ).…”

“…TMEM165 deficiency has mostly been associated with N-, O -glycosylation defects, with increased undersialylated and undergalactosylated glycans, as well as in high mannose type N-Glycan detected in patient serum compared with healthy control (Foulquier et al, 2012 ; Xia et al, 2013 ; Zeevaert et al, 2013 ). However, recently, an abnormal migration profile of bikunin bearing CS chain was observed on a Western blot on patient serum (Haouari et al, 2020 ). Moreover, tmem165 deficiency in zebrafish led to alterations in CS PG expression detected by immunohistochemical staining of cartilage (Bammens et al, 2015 ).…”