title: Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases.
abstract: We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (~0.1 %) of European SCA cases.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Oostersingel Entrance 47, P.O. Box 30 001, 9700 RB Groningen, The Netherlands.
authors.forename: Justyna
authors.initials: J
authors.lastname: Jezierska
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Michiel R
authors.initials: MR
authors.lastname: Fokkens
authors.forename: Fabien
authors.initials: F
authors.lastname: Zagnoli
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kok
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Goas
authors.forename: Pierre
authors.initials: P
authors.lastname: Bertrand
authors.forename: Christophe
authors.initials: C
authors.lastname: Robin
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Dineke S
authors.initials: DS
authors.lastname: Verbeek
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002524:Cerebellar Ataxia / Q000235:genetics*; D004745:Enkephalins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics*
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin