title: PKD2 mutation in an Iranian autosomal dominant polycystic kidney disease family with misleading linkage analysis data.
abstract: BACKGROUND
  Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder caused by mutation in 2 genes PKD1 and PKD2. Thus far, no mutation is identified in approximately 10% of ADPKD families, which can suggest further locus heterogeneity. Owing to the complexity of direct mutation detection, linkage analysis can initially identify the responsible gene in appropriate affected families. Here, we evaluated an Iranian ADPKD family apparently unlinked to both PKD1 and PKD2 genes. This is one of the pioneer studies in genetic analysis of ADPKD in Iranian population.
  
  
  METHODS
  Linkage reanalysis was performed by regenotyping of flanking microsatellite markers in 8 individuals of the ADPKD family. Direct mutation analysis was performed by Sanger sequencing.
  
  
  RESULTS
  Mutation analysis revealed a pathogenic mutation (c.1094+1G>A) in the PKD2 gene in the proband. Analyzing 2 healthy and 4 clinically affected members confirmed the correct segregation of the mutation within the family and also ruled out the disease in 1 suspected individual. Misinterpretation of the linkage data was due to the occurrence of 1 crossing over between the PKD2 intragenic and the nearest downstream marker (D4S2929). Homozygosity of upstream markers caused the recombination indistinguishable.
  
  
  CONCLUSIONS
  Although analysis of additive informative polymorphic markers can overcome the misleading haplotype data, it is limited because of the lack of other highly polymorphic microsatellite markers closer to the gene. Direct mutation screening can identify the causative mutation in the apparently unlinked pedigree; moreover, it is the only approach to achieve the confirmed diagnosis in individuals with equivocal imaging results.
authors.affiliation: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mona
authors.initials: M
authors.lastname: Entezam
authors.affiliation: Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Khatami
authors.affiliation: School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Fereshteh
authors.initials: F
authors.lastname: Saddadi
authors.affiliation: Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ayati
authors.affiliation: Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Roozbeh
authors.affiliation: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Keramatipour
keywords: Autosomal dominant polycystic kidney disease; Linkage analysis; Mutation screening; Recombination