Novel PKD2 Missense Mutation p.Ile424Ser in an Individual with Multiple Hepatic Cysts: A Case Report

Abstract

We report a novel missense mutation, p.Ile424Ser, in the PKD2 gene of an autosomal dominant polycystic kidney disease (ADPKD) patient with multiple liver cysts. A 57-year-old woman presented to our university hospital with abdominal fullness, decreasing appetite, and dyspnea for three months. A percutaneous drainage of hepatic cysts was performed with no significant symptomatic relief. A computed tomography (CT) scan revealed a hepatic cyst in the lateral portion of the liver with appreciable compression of the stomach. Prior to this admission, the patient had undergone three drainage procedures with serial CT-based follow-up of the cysts over the past 37 years. With a presumptive diagnosis of extrarenal manifestation of ADPKD, we performed both a hepatic cystectomy and a hepatectomy. Because the patient reported a family history of hepatic cysts, we conducted a postoperative genetic analysis. A novel missense mutation, p.Ile424Ser, was detected in the PKD2 gene. Mutations in either the PKD1 or PKD2 genes account for most cases of ADPKD. To the extent of our knowledge, this point mutation has not been reported in the general population. Our in-silico analysis suggests a hereditary likely pathogenic mutation.

Keywords: PKD2 (polycystic kidney disease type 2); autosomal dominant polycystic kidney disease (ADPKD); estrogen; polycystic liver.

Figure 1

Magnetic resonance imaging of the polycystic liver performed during the patient’s first visit. (a) Axial T2-weighted image. (b) Magnetic resonance cholangiopancreatography revealed intracystic heterogeneity and septation with associated focal hyperintensity, suggestive of intracystic bleeding (red arrows). Extrahepatic cysts compress the stomach (yellow arrowheads).

Figure 2

Surgical findings. (a) Multiple hepatic cysts occupy the upper abdominal cavity. Extrahepatic cysts compress the stomach (yellow arrowheads). (b) Intracystic bleeding scars are present. Intraoperative cytological analysis of the cyst content was negative for malignancy (red arrows). (c) Abdominal cavity after cystectomy and hepatectomy.

Figure 3

Genetic analysis reveals a novel missense mutation in the PKD2 gene of the patient. DNA sequence codes: A (adenine), C (cytosine), G (guanine), T (thymine) and K (T or G). Red asterisk indicates T to G mutation. Black asterisk is wild-type gene sequence, on the same position as red asterisk. The DNA sequence of the patient has one allele wild type T and the other has a mutation G. The upper numbers 422 to 426 indicate aa (amino acid) residue of PC2.

Figure 4

Signaling pathways involved in autosomal dominant polycystic kidney disease (ADPKD) pathogenesis. ADPKD is caused by mutations in PKD1 and PKD2, which code for the polycystin proteins PC1 and PC2, respectively, which form heterodimers in the cilia of cells. PC1 and PC2 have been reported to function in various signaling pathways. PC1 and PC2 bind and form part of a protein complex found in the primary cilium that operates as a flow-regulated Ca²⁺ channel. Defects in any of the complex proteins reduce Ca²⁺ influx and lead to low Ca²⁺ intracellular concentrations. The PC1/PC2 complex interacts with and activates JAK2, which phosphorylates STAT. STAT normally inhibits the cyclin/CDK pathways, which promote cell cycle progression; hence, its downregulation in ADPKD would increase epithelial cell proliferation. PC1 and PC2 signal via G proteins and distinct PKC isoforms to activate JNK and p38, which in turn stimulate transcription factor AP1. Estrogen, acting through the cell membrane and cytosolic/nuclear receptors (ER), can also stimulate cell proliferation. This figure is adapted from Figure 1 in a previous study, “Somatostatin, estrogen, and polycystic liver disease” [19]. Modified and reprinted from ref [19] Copyright (2013), with permission from Elsevier [License Number: 5275740748526].