title: Mutation detection in the duplicated region of the polycystic kidney disease 1 (PKD1) gene in PKD1-linked Australian families.
abstract: Screening for disease-causing mutations in the duplicated region of the PKD1 gene was performed in 17 unrelated Australian individuals with PKD1-linked autosomal dominant polycystic kidney disease. Exons 2-21 and 23-34 were assayed using PKD1-specific PCR amplification and direct sequencing. We have identified 12 novel probably pathogenic DNA variants, including five truncating mutations (Q563X, c.5105delAT, c.5159delG, S2269X, c.9847delC), two in-frame deletions (c.7472del3, c.9292del39), and two splice-site mutations (IVS14+1G>C, IVS16+1G>T). Three of the mutations (G381C, Y2185D, G2785D) were predicted to lead to the replacement of conserved amino acid residues, with ensuing changes in protein conformation. Defects in the duplicated region of PKD1 thus account for 63% of our patients. Together with the previously detected mutations (Q4041X, R4227P) in the 3 region of the gene, the study has achieved an overall mutation detection rate of 74%. In addition, we have detected 31 variants (nine novel and 22 previously published) that did not segregate with the disease and were considered to be neutral polymorphisms. Three of the nine novel polymorphisms were missense mutations with a predicted effect on protein conformation, emphasizing the problems of interpretation in PKD1 mutation screening.
authors.affiliation: Centre for Human Genetics, Edith Cowan University, Joondalup, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: McCluskey
authors.forename: Tina
authors.initials: T
authors.lastname: Schiavello
authors.forename: Michael
authors.initials: M
authors.lastname: Hunter
authors.forename: Janina
authors.initials: J
authors.lastname: Hantke
authors.forename: Dora
authors.initials: D
authors.lastname: Angelicheva
authors.forename: Nadja
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Arseni
authors.initials: A
authors.lastname: Markoff
authors.forename: Mark
authors.initials: M
authors.lastname: Thomas
authors.forename: Bernd
authors.initials: B
authors.lastname: Dworniczak
authors.forename: Juergen
authors.initials: J
authors.lastname: Horst
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001315:Australia; D004252:DNA Mutational Analysis; D020440:Gene Duplication; D008040:Genetic Linkage / Q000235:genetics*; D005973:Glutamine; D006801:Humans; D008715:Methionine; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D007690:Polycystic Kidney Diseases / Q000235:genetics; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment; D050396:TRPP Cation Channels; D013912:Threonine
chemical_list: D005973:Glutamine; D008715:Methionine; D011506:Proteins; D050396:TRPP Cation Channels; D013912:Threonine