A Presumed Synonymous Mutation of PKD2 Caused Autosomal Dominant Polycystic Kidney Disease in a Chinese Family

Abstract

Objective

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by the pathogenic mutation of PKD1 or PKD2 gene and usually affects bilateral kidneys. Synonymous mutations are generally assumed to be neutral as they do not alter amino acids. Herein, we described an extremely rare ADPKD child caused by a heterozygous synonymous mutation of PKD2 gene accompanied by massive proteinuria and congenital solitary kidney.

Methods

Clinical characteristics of the patients were summarized. Whole-exome sequencing was performed to screen the disease-causing gene mutation, and reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were applied to analyze the impact of the identified mutation on gene transcription and splicing.

Results

Polycystic changes were found in the solitary kidney of a girl initially presented with nephrotic-range proteinuria. Thereafter her mother and 2 other family members were diagnosed to be ADPKD. Whole-exome sequencing of the proband identified a heterozygous synonymous mutation (c.1716G>A, p.Lys572=) located in the splicing site of exon 7 in PKD2 gene, which was co-segregated with the PKD phenotype in the family. RT-PCR and direct sequencing of amplified products revealed that this heterozygous synonymous mutation led to exon7 skipping in PKD2 gene.

Conclusion

We reported an extremely rare child case of ADPKD2 in combination with solitary kidney and nephrotic-range proteinuria, and firstly confirmed the pathogenicity of a heterozygous synonymous mutation (c.1716G>A) in PKD2 gene. The results indicate that synonymous mutations should not be excluded from disease-causing if they are located in splicing site of an exon.

Keywords

autosomal dominant polycystic kidney disease / child / PKD2 gene / splicing / synonymous mutation

References

[1] BaruaM, PeiY. Diagnosis of Autosomal-Dominant Polycystic Kidney Disease: An Integrated Approach. Semin Nephrol, 2010, 30(4): 356-365

[2] RossettiS, ConsugarMB, ChapmanAB, et al.. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol, 2007, 18(7): 2143-2160

[3] Cornec-Le GallE, AudrezetMP, ChenJM, et al.. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol, 2013, 24(6): 1006-1013

[4] VesterU, KranzB, HoyerPF. The diagnostic value of ultrasound in cystic kidney diseases. Pediatr Nephrol, 2010, 25(2): 231-240

[5] ChapmanAB, JohnsonAM, GabowPA, et al.. Overt proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease. J Am Soc Nephrol, 1994, 5(6): 1349-1354

[6] HoffmeisterH, GallagherAR, RascleA, et al.. The human polycystin-2 protein represents an integral membrane protein with six membrane-spanning domains and intracellular N- and C-termini. Biochem J, 2011, 433(2): 285-294

[7] NauliSM, AlenghatFJ, LuoY, et al.. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet, 2003, 33(2): 129-137

[8] RichardsS, AzizN, BaleS, et al.. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015, 17(5): 405-424

[9] Gonzalez-ParedesFJ, Ramos-TrujilloE, Claverie-MartinF. Three exonic mutations in polycystic kidney disease-2 gene (PKD2) alter splicing of its pre-mRNA in a minigene system. Gene, 2016, 578(1): 117-123

[10] WaterhouseA, BertoniM, BienertS, et al.. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res, 2018, 46(W1): W296-W303

[11] SaunaZE, Kimchi-SarfatyC. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet, 2011, 12(10): 683-691

[12] BurattiE, BaralleM, BaralleFE. Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res, 2006, 34(12): 3494-3510

[13] AnnaA, MonikaG. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet, 2018, 59(3): 253-268

[14] HackmannK, MarkoffA, QianF, et al.. A splice form of polycystin-2, lacking exon 7, does not interact with polycystin-1. Hum Mol Genet, 2005, 14(21): 3249-3262

[15] BaralleFE, GiudiceJ. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol, 2017, 18(7): 437-451

[16] RossettiS, KublyVJ, ConsugarMB, et al.. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int, 2009, 75(8): 848-855

[17] TanYC, BlumenfeldJ, MichaeelA, et al.. Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease. Clin Genet, 2011, 80(3): 287-292

[18] GriebenM, PikeAC, ShintreCA, et al.. Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat Struct Mol Biol, 2017, 24(2): 114-122

[19] WieselA, Queisser-LuftA, ClementiM, et al.. Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries. Eur J Med Genet, 2005, 48(2): 131-144

[20] NicolaouN, RenkemaKY, BongersEM, et al.. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol, 2015, 11(12): 720-731

[21] PosterD, KistlerAD, KrauerF, et al.. Kidney function and volume progression in unilateral autosomal dominant polycystic kidney disease with contralateral renal agenesis or hypoplasia: a case series. Am J Kidney Dis, 2009, 54(3): 450-458

[22] PecesR, VegaC, AguilarA, et al.. Autosomal dominant polycystic kidney disease with contralateral renal agenesis. Nefrologia, 2012, 32(6): 839-842

[23] JeongGH, ParkBS, JeongTK, et al.. Unilateral autosomal dominant polycystic kidney disease with contralateral renal agenesis: a case report. J Korean Med Sci, 2003, 18(2): 284-286

[24] BearRA. Solitary Kidney Affected with Polycystic Disease: A Report of 2 Cases. J Urology, 1974, 111(5): 566-567

[25] SirventAE, EnriquezR, ArdoyF, et al.. Autosomal dominant polycystic kidney disease with congenital absence of contralateral kidney. Int Urol Nephrol, 2006, 38(3–4): 773-774

[26] TodorovVV. The diagnostic dilemma of the unilateral cystic kidney-ADPKD with aplasia of one kidney. Nephrol Dial Transplant, 1999, 14(11): 2775

[27] KrzemienG, TurczynA, Panczyk-TomaszewskaM, et al.. Long-term follow up of a boy with unilateral autosomal dominant polycystic kidney disease and contralateral renal agenesis. Dev Period Med, 2017, 21(4): 380-383

[28] ViscianoB, Di PietroRA, RossanoR, et al.. Nephrotic syndrome and autosomal dominant polycystic kidney disease. Clin Kidney J, 2012, 5(6): 508-511

[29] SiomouE, JarvisJ, HultonSA. Autosomal dominant polycystic kidney disease (ADPKD) associated with steroid-sensitive nephrotic syndrome in childhood. Pediatr Nephrol, 2011, 26(4): 643-644

[30] KiprovDD, ColvinRB, McCluskeyRT. Focal and segmental glomerulosclerosis and porteinuria associated with unilateral renal agenesis. Lab Invest, 1982, 46(3): 275-281

[31] ThornerPS, ArbusGS, CelermajerDS, et al.. Focal segmental glomerulosclerosis and progressive renal failure associated with a unilateral kidney. Pediatrics, 1984, 73(6): 806-810

[32] Gutierrez-MilletV, NietoJ, PragaM, et al.. Focal glomerulosclerosis and proteinuria in patients with solitary kidneys. Arch Intern Med, 1986, 146(4): 705-709

[33] OshiroY, UmenaS, NodaM. Focal segmental glomerulosclerosis complicating solitary kidney. Clin Exp Nephrol, 2009, 13(1): 81-84