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Hum Mutat. 2009 Apr;30(4):583-9. doi: 10.1002/humu.20872.

Systemic hyalinosis mutations in the CMG2 ectodomain leading to loss of function through retention in the endoplasmic reticulum.

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  • 1Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.


Systemic hyalinosis is an autosomal recessive disease that encompasses two allelic syndromes, infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF), which are caused by mutations in the CMG2 gene. Here we have analyzed the cellular consequences of five patient-derived point mutations in the extracellular von Willebrand domain or the transmembrane domain of the CMG2 protein. We found that four of the mutations led to retention of the protein in the endoplasmic reticulum (ER), albeit through different mechanisms. Analysis of recombinant CMG2 von Willebrand factor A (vWA) domains, to which three of the mutations map, indicated that the mutations did not prevent proper folding and ligand binding, suggesting that, in vivo, slow folding, rather than misfolding, is responsible for ER retention. Our work shows that systemic hyalinosis can be qualified as a conformational disease, at least for the mutations that have been mapped to the extracellular and transmembrane domains. The long ER half-life and the ligand binding ability of the mutated von Willebrand domains suggest that treatments based on chemical chaperones could be beneficial.

(c) 2009 Wiley-Liss, Inc.

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