Human Molecular Genetics Advance Access originally published online on June 3, 2009
Human Molecular Genetics 2009 18(17):3244-3256; doi:10.1093/hmg/ddp262
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Golgi function and dysfunction in the first COG4-deficient CDG type II patient
1 Laboratory for Membrane Trafficking, Center for Human Genetics, University of Leuven and Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium 2 Laboratoire de Glycobiologie Structurale et Functionelle, USTL, Lille, France 3 Department of Pediatrics, San João Hospital, Porto, Portugal 4 Institute of Medical Genetics Jacinto de Magalhães, Porto, Portugal 5 Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, The Cell Microscopy Center, Utrecht, The Netherlands 6 Laboratory for Molecular Diagnosis, Center for Human Genetics, University of Leuven, B-3000 Leuven, Belgium
* To whom correspondence should be addressed at: Center for Human Genetics, KULeuven, Herestraat 49, B-3000 Leuven, Belgium (GM.)/Center for Human Genetics, KULeuven, and Department of Molecular and Developmental Genetics, VIB, Herestraat 49, B-3000 Leuven, Belgium (W.A.). Tel: +32 16346070 (G.M.)/+32 16330520 (W.A.); Fax: +32 16346060 (G.M.)/+32 16330522 (W.A.); Email: gert.matthijs{at}uz.kuleuven.be (G.M.)/wim.annaert{at}cme.vib-kuleuven.be (W.A.)
Received January 27, 2009; Accepted June 1, 2009
The conserved oligomeric Golgi (COG) complex is a hetero-octameric complex essential for normal glycosylation and intra-Golgi transport. An increasing number of congenital disorder of glycosylation type II (CDG-II) mutations are found in COG subunits indicating its importance in glycosylation. We report a new CDG-II patient harbouring a p.R729W missense mutation in COG4 combined with a submicroscopical deletion. The resulting downregulation of COG4 expression additionally affects expression or stability of other lobe A subunits. Despite this, full complex formation was maintained albeit to a lower extent as shown by glycerol gradient centrifugation. Moreover, our data indicate that subunits are present in a cytosolic pool and full complex formation assists tethering preceding membrane fusion. By extending this study to four other known COG-deficient patients, we now present the first comparative analysis on defects in transport, glycosylation and Golgi ultrastructure in these patients. The observed structural and biochemical abnormalities correlate with the severity of the mutation, with the COG4 mutant being the mildest. All together our results indicate that intact COG complexes are required to maintain Golgi dynamics and its associated functions. According to the current CDG nomenclature, this newly identified deficiency is designated CDG-IIj.
The authors wish it to be known that, in their opinion, the first two and last two authors should be regarded as joint First/Last Authors.
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