Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke

Murray, L.S., Lu, Y., Taggart, A., Van Regemorter, N., Vilain, C., Abramowicz, M., Kadler, K.E. and Van Agtmael, T. (2014) Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke. Human Molecular Genetics, 23(2), pp. 283-292. (doi: 10.1093/hmg/ddt418) (PMID:24001601) (PMCID:PMC3869351)

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Abstract

Haemorrhagic stroke accounts for approximately 20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance. COL4A2 is the obligatory protein partner of COL4A1 but in contrast to most COL4A1 mutations, the COL4A2 mutation does not lead to eye or kidney disease. Analysis of dermal biopsies from patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects. Intriguingly, defective collagen IV incorporation into the dermal BM was only observed in the patient and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts. This intracellular accumulation led to ER-stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis. Interestingly, absence of ER retention of COL4A2 and ER-stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development. Our analysis also revealed that mutant collagen IV is degraded via the proteasome. Importantly, treatment of patient cells with a chemical chaperone decreased intracellular COL4A2, ER-stress and apoptosis, demonstrating that reducing intracellular collagen accumulation can ameliorate the cellular phenotype of COL4A2 mutations. Importantly, these data highlight that manipulation of chaperone levels, intracellular collagen accumulation and ER-stress are potential therapeutic options for collagen IV diseases including haemorrhagic stroke.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Van Agtmael, Dr Tom and Taggart, Ms Aislynn
Authors: Murray, L.S., Lu, Y., Taggart, A., Van Regemorter, N., Vilain, C., Abramowicz, M., Kadler, K.E., and Van Agtmael, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:02 September 2013
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Human Molecular Genetics
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
471511Collagen type IV in vascular biologyTom Van AgtmaelMedical Research Council (MRC)G0601268RI CARDIOVASCULAR & MEDICAL SCIENCES