title: Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase.
abstract: 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).
authors.affiliation: Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA.
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.forename: Amanda
authors.initials: A
authors.lastname: Leung
authors.forename: Yang Hoon
authors.initials: YH
authors.lastname: Huh
authors.forename: Eungi
authors.initials: E
authors.lastname: Yang
authors.forename: Deog-Joong
authors.initials: DJ
authors.lastname: Kim
authors.forename: Pierre
authors.initials: P
authors.lastname: Leblanc
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Emily M
authors.initials: EM
authors.lastname: Garland
authors.forename: Satish R
authors.initials: SR
authors.lastname: Raj
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003451:Cryoprotective Agents / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005990:Glycerol / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009154:Mutation; D009638:Norepinephrine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D003451:Cryoprotective Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D004299:Dopamine beta-Hydroxylase; D005990:Glycerol; D009638:Norepinephrine