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Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase.

Authors: Kim, CH  Leung, A  Huh, YH  Yang, E  Kim, DJ  Leblanc, P  Ryu, H  Kim, K  Kim, DW  Garland, EM  Raj, SR  Biaggioni, I  Robertson, D  Kim, KS 
Citation: Kim CH, etal., J Biol Chem. 2011 Mar 18;286(11):9196-204. Epub 2011 Jan 5.
Pubmed: (View Article at PubMed) PMID:21209083
DOI: Full-text: DOI:10.1074/jbc.M110.192351

Human norepinephrine (NE) deficiency (or dopamine beta-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable. Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1+2T-->C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Here, we show that the IVS1+2T-->C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER). Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s).


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RGD Object Information
RGD ID: 5685690
Created: 2012-01-17
Species: All species
Last Modified: 2012-01-17
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.