Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1

Abstract

We describe two patients with a cerebrocostomandibular-like syndrome and a novel mutation in conserved oligomeric Golgi (COG) subunit 1, one of the subunits of the conserved oligomeric Golgi complex. This hetero-octameric protein complex is involved in retrograde vesicular trafficking and glycosylation. We identified in both patients an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7. Real-time reverse transcriptase polymerase chain reaction showed in the first patient only 3% of normal transcript when compared with control. A delay in retrograde trafficking could be demonstrated by Brefeldin A treatment of this patient's fibroblasts. The costovertebral dysplasia of the two patients has been described in cerebrocostomandibular syndrome (CCMS), but also in cerebrofaciothoracic dysplasia and spondylocostal dysostosis. CCMS itself is heterogeneous because both autosomal dominant and autosomal recessive inheritance has been described. We anticipate further genetic heterogeneity because no mutations in COG1 were found in two additional patients with a CCMS.

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

“…Skeletal manifestations are an important/predominant part of the phenotype in only about 20 % of the known CDG: EXT1/EXT2-CDG (Jennes et al 2009), B4GALT7 (Seidler et al 2006), B3GAT3-CDG (Baasanjar et al 2011), GALNT3-CDG (Chefetz and Sprecher 2009), SLC35D1-CDG (Hiraoka et al 2007), LFNG-CDG (Sparrow et al 2006), PIGV-CDG (Horn et al 2011), autosomal recessive cerebrocostomandibular like syndrome due to COG1-CDG (Zeevaert et al 2009), and ATP6V0A2-CDG (Guillard et al 2009). The spectrum of these skeletal manifestations is very broad which can be explained by the fact that glycosylation is an important posttranslational modification of numerous proteins, including extracellular matrix proteins and proteins involved in bone metabolism, for example, collagen I (Coman et al 2007) and FGFR-3 (Winterpacht et al 2000).…”

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

“…The identification of milder cases of COG6 and COG7 deficiency harboring different mutations [56,57] however shows that the severity of the disease does not simply relate to the subunit affected but rather to the capability of forming a fully functional COG complex. Besides the severe diseases observed for COG6 and COG7 defects, moderate clinical manifestations have been associated with mutations in COG1 [58,59], COG2 [60], COG4 [61,62], and COG5 [63][64][65].…”

“…The identification of milder cases of COG6 and COG7 deficiency harboring different mutations [56,57] however shows that the severity of the disease does not simply relate to the subunit affected but rather to the capability of forming a fully functional COG complex. Besides the severe diseases observed for COG6 and COG7 defects, moderate clinical manifestations have been associated with mutations in COG1 [58,59] COG subunits build a complex of two lobes, including COG1 to COG4 in lobe A and COG5 to COG8 in lobe B (Figure 4). In general, defects in lobe A lead to milder disease than defects in lobe B. Lobe A appears to be important for overall Golgi architecture, playing a role in Golgi organization and cisGolgi sorting [66].…”

Diseases of glycosylation beyond classical congenital disorders of glycosylation

“…Accordingly, the defective assembly of the Conserved Oligomeric Golgi (COG) complex leads to mislocalization of several glycosyltransferases and thereby to defects in multiple classes of glycosylation [101]. To date, mutations have been found in five of the eight subunit genes of the complex, namely in the COG1 (OMIM ID: 606973) [102], COG4 (OMIM ID: 606976) [103], COG5 (OMIM ID: 606821) [104], COG7 (OMIM ID: 606978) [105] and COG8 (OMIM ID: 606979) subunits [106]. The clinical pictures of COG defects are variable but in general similar to those of other types of CDG with mainly neuromuscular involvements, dysmorphia, psychomotor retardation and coagulopathy [107].…”