Human Molecular Genetics Advance Access published online on November 13, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn379
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Cerebrocostomandibular-like syndrome and a mutation in the Conserved Oligomeric Golgi complex, subunit 1
1 Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium 2 Center for Human Genetics, University of Leuven, Leuven, Belgium 3 Unité de Glycobiologie Structurale et Fonctionnelle UMR/CNRS 8576, IFR147, Université des Sciences et Technologies, Lille, France 4 Laboratory for Membrane Trafficking, Center for Human Genetics, University of Leuven and Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium 5 Clinical Genetics Unit, Department of Pediatrics, Medical faculty, Sofia, Bulgaria
* To whom correspondence should be addressed at: Department of Pediatrics, University Hospitals Leuven, Herestraat 49, BE-3000 Leuven. Tel +32 16343820; Fax +32 16343842; Email: Jaak.Jaeken{at}uz.kuleuven.be
Received August 13, 2008; Revised November 6, 2008; Accepted November 6, 2008
We describe two patients with a cerebrocostomandibular-like syndrome and a novel mutation in COG1, 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 RT-PCR showed in the first patient only 3% of normal transcript compared to 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, but also in cerebrofaciothoracic dysplasia and spondylocostal dysostosis. Cerebrocostomandibular syndrome 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 cerebrocostomandibular syndrome.
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