Mutation Detection of PKD1 Identifies a Novel Mutation Common to Three Families with Aneurysms and/or Very-Early-Onset Disease

Abstract

It is known that several of the most severe complications of autosomal-dominant polycystic kidney disease, such as intracranial aneurysms, cluster in families. There have been no studies reported to date, however, that have attempted to correlate severely affected pedigrees with a particular genotype. Until recently, in fact, mutation detection for most of the PKD1 gene was virtually impossible because of the presence of several highly homologous loci also located on chromosome 16. In this report we describe a cluster of 4 bp in exon 15 that are unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11-21 by use of long-range PCR. The two templates described were used to analyze 35 pedigrees selected for study because they included individuals with either intracranial aneurysms and/or very-early-onset disease. We identified eight novel truncating mutations, two missense mutations not found in a panel of controls, and several informative polymorphisms. Many of the polymorphisms were also present in the homologous loci, supporting the idea that they may serve as a reservoir for genetic variability in the PKD1 gene. Surprisingly, we found that three independently ascertained pedigrees had an identical 2-bp deletion in exon 15. This raises the possibility that particular genotypes may be associated with more-severe disease.

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian (Madurai) Population

“…T/T: homozygous mutant; /T: heterozygous mutant; C/C: homozygous normal. The study coincides with the work of Constantinides et al [70], Watnick et al [79] and Koptides et al, [30] in Caucasians, Greek-Cypriot populations. The present study reveals that these mutation/polymorphism leads to evolution of new alleles and formation of new amino acids among South Indian population.…”

A Pkd1-Fbn1 Genetic Interaction Implicates TGF-β Signaling in the Pathogenesis of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease

“…In support of this idea there are reports of multiple independent families with aneurysms and the same 2 bp deletion in Pkd1 exon 15. 54,55 Not all members of these families, however, present with vascular phenotypes. One possibility is that genetic modifiers that upregulate the TGF-b signaling pathway might also increase the chance of aortic aneurysm in affected individuals.…”

The genetics of intracranial aneurysms

“…The relative risk is increased for a ruptured aneurysm in the classic and vascular types of EDS (type I/II and IV) and autosomal dominant polycystic kidney disease (ADPKD1 and ADPKD2) (Watnick et al 1999;Nekrysh 2000;Hademenos et al 2001). IAs occur in about 8% of ADKPD patients (Gibbs et al 2004) and recur frequently in ADKPD patients with known aneurysms, particularly if there is a positive family history (Ruggieri et al 1994;Belz et al 2003).…”