Norepinephrine Deficiency Is Caused by Combined Abnormal mRNA Processing and Defective Protein Trafficking of Dopamine β-Hydroxylase

• Published in: The Journal of biological chemistry Vol. 286; no. 11; pp. 9196 - 9204
• Main Authors: Kim, Chun-Hyung, Leung, Amanda, Huh, Yang Hoon, Yang, Eungi, Kim, Deog-Joong, Leblanc, Pierre, Ryu, Hoon, Kim, Kyungjin, Kim, Dong-Wook, Garland, Emily M., Raj, Satish R., Biaggioni, Italo, Robertson, David, Kim, Kwang-Soo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Autonomic Nervous System Diseases - drug therapy; Autonomic Nervous System Diseases - enzymology; Autonomic Nervous System Diseases - genetics; CHO Cells; Cricetinae; Cricetulus; Cryoprotective Agents - pharmacology; Dopamine beta-Hydroxylase; Dopamine beta-Hydroxylase - biosynthesis; Dopamine beta-Hydroxylase - deficiency; Dopamine beta-Hydroxylase - genetics; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - genetics; Genetic Diseases; Glycerol - pharmacology; Heat-Shock Proteins - biosynthesis; Heat-Shock Proteins - genetics; Humans; Intracellular Trafficking; Missense Mutations; Molecular Bases of Disease; Mutant; Mutation; NE Deficiency; Neurobiology; Neurotransmitters; Norepinephrine - deficiency; Norepinephrine - genetics; Norepinephrine - metabolism; Protein Transport - drug effects; Protein Transport - genetics; RNA Processing, Post-Transcriptional; RNA Splice Sites; RNA, Messenger - genetics; RNA, Messenger - metabolism; Splice Mutation; NE Deficiency; Neurotransmitters; Missense Mutations; Genetic Diseases; Mutant; Neurobiology; Splice Mutation; Intracellular Trafficking; Dopamine beta-Hydroxylase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.192351

Human norepinephrine (NE) deficiency (or dopamine β-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).