One of the most prevalent inherited kidney disorders that involves both kidneys is autosomal dominant polycystic kidney disease (ADPKD) which leads to a progressive loss of kidney function and possible kidney failure (1). About one to two infants in 1000 live at birth, and approximately 10% of people who undergo dialysis are affected by this disease (2, 3). ADPKD occurs in two types of type I and type II caused by PKD1 and PKD2 mutations, respectively (4, 5).
PKD2 mutation causes end-stage renal disease at an average age of 74 years and occurs in 10-15% of cases; on the other hand, PKD1 mutation leads to end-stage renal disease at an average age of 54years wich occurs in 80-90 % of total casesod ADPKD. The latter is the more severe form of the disease (1, 3, 5). Patients having end-stage kidney disease should receive renal replacement therapy (RRT) or dialysis to stay alive. However, dialysis has limitations, including lack of vascular access, risks of vascular thrombosis and infections, diminished quality of life, and loss of the kidney biosynthetic functions (6). Patients whowere diagnosed with ADPKD before age 30 and hypertension and hematuria before age 35, have a worse renal outcome (7). ADPKD diagnosis is typically done by kidney ultrasound imaging, computed tomography scan or magnetic resonance imaging; however, considering the ADPKD similarity to other cystic kidney disorders, conventional imaging methods do not often end up with a definite diagnosis (1, 2) Additionaly, molecular methods have an important role confirming ADPKD diagnosis, especially in young kidney donors, patients with negative family history, people who presented ADPKD with unusual symptoms in childhood and patients who have relatives suffering from this disorder (8, 9).
ADPKD is the most frequent genetic kidney pathology (frequency of about 0.1%), which results in 5% - 8% of end-stage renal diseases (ESRDs). ESRD is progressive, ending in enlarged polycystic kidneys typically occuring in late middle age (5). Polycystin-1, is a large multidomain protein encoded by PKD1. It has domains and regions that are homologous with a number of different proteins (10). Polycystin- 1 has been proposed to act as a G protein–coupled receptor (11). Instead, polycystin-2 (the protein coded by PKD2) is homologous to an ion-channel subunit (12,13). Most cases of ADPKD leading to ESRD are caused by PKD1 mutations (14). Nevertheless, the genetic determination of the locus mutation has advanced slowly, due to the fact that PKD1 contains a 12,906-bp coding sequence divided into 46 exons and that the the 5′ region of the gene, from upstream of exon 1 to exon 33, is inserted in a complex genomic area and repeated more than 4 times on the same chromosome (15). The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Homologous sequences searches in a number of databases have found one partial cDNA and two genomic sequences with significant homology to both polycystin-1 and -2 (16)
ThePKD1-like homologous gene (HG) has revealed a number of specific deletions and a low level of substitutions (about 2%) in comparison with PKD1 (17). The HG locus analysis of PKD1 has been highly difficult. Thus, the quantity of identified PKD1 mutations is still incomplete, with 82 modifications described in the Online Human Gene Mutation Database (HGMD) (18). A multiple number of methods have been used to screen the repeated region (19-23), however, the 3′ area has received insufficient attention, with 57.3% of all mutations found in the single-copy area covering 20% of the coding region. PKD2 (a less-complex gene) has revealed 41 mutations with potential effects of truncating and possibly inactivating the translated protein (24). A discrete number of missense changes have also been described (19, 23- 26). Since numerous somatic mutations and a significant rate of formation of novel germline mutations are needed to explain cystogenesis (19), it has been proposed that infrequent mechanisms promote a high rate of PKD1 mutations. A long polypyrimidine region in IVS21, which could theoretically form triplex DNA structures (27, 28), has been considered as a possible cause downstream exons mutations (22). These multiple substitutions and other modifications were described to match HG sequences, possibly indicating a gene conversion with the remotely located HG loci (21, 29). PKD1 gene (OMIM 601313) is located in the 16p13.3 chromosome region and consists of 46 exons. Exons 1-33 of PKD1 replicate around 6 times in homologous genes (HG), which has challenged PKD1 genetic analysis. Until January 2015, approximately 2322 PKD1 sequence variants and 278 PKD2 sequence variants were reported in ADPKD mutation databases, 1177 PKD1 sequence, and 211 PKD2 sequences in human gene mutation (16, 17). Although mutation data for PKD genes of different populations are available, there are few reports for PKD mutations in Iranian population. The main goal of this study was to establish the frequency of mutations in the PKD1 gene obtained by PCR (Polymerase Chain Reaction) and DNA Sanger sequencing (30) in Iranian patients with ADPKD diagnosis.