One of the most prevalent inherited kidney disorders that involves both kidneys is Autosomal dominant polycystic kidney disease (ADPKD). It leads to a progressive loss of kidney function and possible kidney failure (1). About one to two infants in 1000 live at birth are affected by this disorder and approximately 10% of people who undergo dialysis; suffer from this disease (2, 3). ADPKD occurs in two types: type I and type II caused by PKD1 and PKD2 mutations, respectively (4, 5).
PKD2 mutations lead to end-stage kidney or renal disease at age 74 and occur in 10-15% of cases; on the other hand, PKD1 mutations lead in the average to end-stage kidney or renal disease at age 54.3 and occur in 80-90 % of total cases. The latter is the more severe form of the disease (1, 3, 5). Patients having end-stage kidney or renal disease should receive renal replacement therapy (RRT) support including dialysis and renal transplantation. Dialysis may be the only available modality in these patients. After all, dialysis has its limitations, including sometimes lack of vascular access, risks of vascular thrombosis and infections, diminished quality of life, and loss of biosynthetic functions of the kidney (6). ADPKD patients who have diagnosed before age 30 and hypertension and hematuria before age 35 have a worse renal outcome than those who do not have (7). ADPKD diagnosis is done typically 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 lead to a definite and accurate diagnosis (1, 2). In this condition, genetic methods can be effective in an accurate and careful diagnosis. Besides, molecular diagnosis methods have an important role in the confirmation of definite 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). The ailment is progressive, ending in polycystic enlarged kidneys. This typically results in ESRD in late middle age (5). Polycystin-1, large multidomain protein, is the protein encoded by PKD1. It has domains and regions that are homologous with a number of different proteins (10). International Polycystic Kidney Disease Consortium 1995(11,12). Polycystin- 1 may have a function in cell-cell/matrix interactions (13) instead, polycystin-2 (the PKD2 protein) is homologous to an ion-channel subunit (14,15). Most cases of ADPKD leading to ESRD, are caused by PKD1 mutations (16). Nevertheless, the genetic determination of the locus mutation has advanced slowly, due to the fact that (1) PKD1 contains a 12,906-bp coding sequence divided into 46 exons (2) and, 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 (European Polycystic Kidney Disease Consortium 1994). These PKD1-like homologous genes (HG) have revealed a number of specific deletions and a low level of substitutions (about 2%), in comparison with PKD1 (17). HG loci have made the analysis of PKD1 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 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 are needed to explain the formation of multiple cysts and the notion of a significant rate of formation of novel germline mutations (19), it has been proposed that infrequent mechanisms promote a high rate of PKD1 mutations. First, a long polypyrimidine region in IVS21, which could theoretically form triplex DNA structures (27, 28), has been considered as a possible cause for creating mutations in downstream exons (22). Later on, 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 defied 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 probability of mutations in PKD1 gene in Iranian patients with ADPKD diagnosis obtained by PCR (Polymerase Chain Reaction) and DNA Sanger sequencing (30).