Neuropediatrics 2017; 48(06): 426-431
DOI: 10.1055/s-0037-1603978
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Different Mutations of Gap Junction Connexin 47 Lead to Discrepant Activation of Unfolded Protein Response Pathway in Pelizaeus–Merzbacher-Like Disease

Na Chen1, 2, Jingmin Wang1, Yuwu Jiang1, Ye Wu1, Hongjun Hao3, Taoyun Ji1
  • 1Department of Pediatrics, Peking University First Hospital, Beijing, China
  • 2Department of Pediatrics, Capital Medical University, Beijing Tian Tan Hospital, Beijing, China
  • 3Department of Neurology, Peking University First Hospital, Beijing, China
Further Information

Publication History

24 February 2017

23 May 2017

Publication Date:
16 July 2017 (eFirst)

Abstract

Background The unfolded protein response (UPR) includes three cascade pathways, which are responsible for the elimination of overload protein that is accumulated in the endoplasmic reticulum (ER). We hypothesize that mutations in connexin 47 (Cx47) lead to abnormal retain of the protein in the ER lumen, which causes Pelizaeus–Merzbacher-like disease (PMLD), a hypomyelinating leukodystrophic disorder.

Methods In this study, the influence of mutant Cx47 on the three UPR cascade pathways and discrepant UPR activation was analyzed in an oligodendrocyte cell line transfected with different mutations in the first extracellular loop of Cx47. As over activated UPR pathway would lead to cell apoptosis, cell viability and apoptosis were also compared between the different mutants.

Results The elevated UPR level accompanied with higher apoptotic rates were measured in the c.138C > G or c.217C > T-transduced oligodendrocytes, but not in the c.216delGinsAA group, compared with the wild-type and empty vector groups. Cell viability was lower in oligodendrocytes transfected with the mutation of c.138C > G or c.217C > T, but not in the c.216delGinsAA group.

Conclusion Different mutations in the Cx47 lead to discrepant activation of UPR pathway, which encouraged apoptotic cell death at different levels. Inappropriate activation of UPR may play important roles in the pathophysiology of PMLD.

Note

The authors declare that they have no competing interests.