Identification of a pathogenic mutation in a Chinese pedigree with polycystic kidney disease

Abstract

Polycystic kidney disease (PKD) is a life-threatening inherited disease with a morbidity of 1:500–1,000 worldwide. Numerous progressively enlarging cysts are observed in the bilateral kidneys of patients with PKD, inducing structural damage and loss of kidney function. The present study analyzed one family with PKD. Whole exome sequencing of the proband was performed to detect the pathogenic gene present in the family. Candidate gene segments for lineal consanguinity in the family were amplified by nest polymerase chain reaction, followed by Sanger sequencing. One novel duplication variant (NM_001009944.2:c.9359dupA:p.Y3120_E3121delinsX) and one missense mutation (c.G9022A:p.V3008M) were detected in PKD1. Additionally, the pathogenic substitutions in PKD1 published from the dataset were analyzed. Following analysis and confirmation, the duplication variant NM_001009944.2:c.9359dupA:p.Y3120_E3121delinsX in PKD1, within the polycystin-1, lipoxygenase, α-toxin domain, was considered to be the pathogenic factor in the examined family with autosomal dominant PKD. Additionally, based on the analysis of 4,805 pathogenic substitutions in PKD1 within various regions, the presence of the missense mutation in the N-terminal domain of polycystin-1 may present high pathogenicity in ADPKD.

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

“…To date, more than 2,000 mutations in PKD1 and about 400 mutations in PKD2 have been identified in people with ADPKD ( Dong et al, 2019 ). Most mutations in PKD1 result in expression of the abnormally small, non-functional PC1 protein, which likely interrupts intracellular and ciliary signaling pathways, resulting in atypical cell growth and proliferation ( Hopp et al, 2012 ; Cai et al, 2014 ; Cebotaru et al, 2014 ; Kurbegovic et al, 2014 ).…”

“…ADPKD is usually diagnosed later in life, while ARPKD develops during prenatal development, or in early childhood. ADPKD is mainly associated with mutations in the PKD1 or PKD2 genes encoding the polycystin-1 and -2 proteins (PC1 and PC2), respectively (Dong et al, 2019). The primary cause of ARPKD is mutations in the PKHD1 gene encoding the fibrocystin/polyductin protein (FPC; Burgmaier et al, 2021).…”

The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus

“…Our data identify PC-1’s CTL domain as an essential component for polycystin activation. Interestingly, the CTL domain is a hotspot for ADPKD-causing mutations ( Dong et al, 2019 ), supporting the critical importance of this domain ( Figure 2—figure supplement 1B ). Although C-type lectins are the most diverse family of mammalian carbohydrate-binding proteins ( Keller and Rademacher, 2020 ), little is known about the function of the CTL motif within PC-1 ( Sandford et al, 1997 ), but it has been reported to bind to carbohydrates in a calcium-dependent manner ( Weston et al, 2001 ).…”

“…* indicates 100% conserved amino acid residues. ( B ) Adhesion domains present in NTF 25-853 and the number and location of ADPKD-causing mutations reported to date (18 mutations have been reported for the CTL domain [ Dong et al, 2019 ]). Sequence alignment of the CTL domain from human PC-1 and PC-1L3.…”

Disease causing property analyzation of variants in 12 Chinese families with polycystic kidney disease

“…The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). Variants are sited in mutational hotspots (Dong et al, 2019), in which pathogenic variants in one or several nearby residues have been observed with greater frequency (PM1). Variants that are absent from gnomAD, 1000 Genome Program and ExAC databases are considered follow a moderate piece of evidence for pathogenicity (PM2).…”