title: Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency.
abstract: Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH.
authors.affiliation: Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cubells
authors.forename: Sonhae
authors.initials: S
authors.lastname: Cho
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000097:blood; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D004837:Epinephrine / Q000097:blood; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009638:Norepinephrine / Q000097:blood / Q000172:deficiency*; D010375:Pedigree
chemical_list: D004247:DNA; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine