title: Functional deficit associated with a missense Werner syndrome mutation.
abstract: Werner syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WRN gene. WRN helicase, a member of the RecQ helicase family, is involved in various DNA metabolic pathways including DNA replication, recombination, DNA repair and telomere maintenance. In this study, we have characterized the G574R missense mutation, which was recently identified in a WS patient. Our biochemical experiments with purified mutant recombinant WRN protein showed that the G574R mutation inhibits ATP binding, and thereby leads to significant decrease in helicase activity. Exonuclease activity of the mutant protein was not significantly affected, whereas its single strand DNA annealing activity was higher than that of wild type. Deficiency in the helicase activity of the mutant may cause defects in replication and other DNA metabolic processes, which in turn could be responsible for the Werner syndrome phenotype in the patient. In contrast to the usual appearance of WS, the G574R patient has normal stature. Thus the short stature normally associated with WS may not be due to helicase deficiency.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Blvd, Suite 100, Baltimore, MD 21224, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tadokoro
authors.forename: Ivana
authors.initials: I
authors.lastname: Rybanska-Spaeder
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kulikowicz
authors.forename: Lale
authors.initials: L
authors.lastname: Dawut
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics; D004277:DNA, Single-Stranded / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding / Q000235:genetics; D053484:RecQ Helicases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014898:Werner Syndrome / Q000175:diagnosis / Q000235:genetics*; D000071657:Werner Syndrome Helicase
chemical_list: D004277:DNA, Single-Stranded; D000255:Adenosine Triphosphate; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase