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

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.

Transcription Factor ß-Catenin Plays a Key Role in Fluid Flow Shear Stress-Mediated Glomerular Injury in Solitary Kidney.

Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function in vivo. FFSS-treated cultured podocytes show upregulated AKT-GSK3ß-ß-catenin signaling. The present study was undertaken to confirm (i) the activation of ß-catenin signaling in podocytes in vivo using unilaterally nephrectomized (UNX) TOPGAL mice with the ß-galactosidase reporter gene for ß-catenin activation, (ii) ß-catenin translocation in FFSS-treated mouse podocytes, and (iii) ß-catenin signaling using publicly available data from UNX mice. The UNX of TOPGAL mice resulted in glomerular hypertrophy and increased the mesangial matrix consistent with hemodynamic adaptation. Uninephrectomized TOPGAL mice showed an increased ß-galactosidase expression at 4 weeks but not at 12 weeks, as assessed using immunofluorescence microscopy (p < 0.001 at 4 weeks; p = 0.16 at 12 weeks) and X-gal staining (p = 0.008 at 4 weeks; p = 0.65 at 12 weeks). Immunofluorescence microscopy showed a significant increase in phospho-ß-catenin (Ser552, p = 0.005) at 4 weeks but not at 12 weeks (p = 0.935) following UNX, and the levels of phospho-ß-catenin (Ser675) did not change. In vitro FFSS caused a sustained increase in the nuclear translocation of phospho-ß-catenin (Ser552) but not phospho-ß-catenin (Ser675) in podocytes. The bioinformatic analysis of the GEO dataset, #GSE53996, also identified ß-catenin as a key upstream regulator. We conclude that transcription factor ß-catenin mediates FFSS-induced podocyte (glomerular) injury in solitary kidney.

Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A case report.

The aetiology of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.

Microarray analysis in pregnancies with isolated unilateral kidney agenesis.

BackgroundThe objective of our study was to examine the risk for submicroscopic chromosomal aberrations among fetuses with apparently isolated solitary kidney.MethodsData acquisition was performed retrospectively by searching Israeli Ministry of Health-computerized database. All cases having chromosomal microarray analysis (CMA), referred because of an indication of isolated unilateral kidney agenesis between January 2013 and September 2016, were included. Rate of clinically significant CMA findings in these pregnancies was compared to pregnancies with normal ultrasound, based on a systematic review encompassing 9,792 cases and local data of 5,541 pregnancies undergoing CMA because of maternal request.ResultsOf the 81 pregnancies with isolated solitary kidney, 2 (2.47%) loss-of-copy number variants compatible with well-described deletion syndromes were reported (16p11.2-16p12.2 and 22q11.21 microdeletion syndromes). In addition, one variant of unknown significance was demonstrated. The relative risk for pathogenic CMA findings among pregnancies with isolated unilateral renal agenesis was not significantly different compared with the control population.ConclusionCMA analysis in pregnancies with unilateral renal agenesis might still be useful, to the same degree as it can be in the general population.

Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis.

BACKGROUND: Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis-related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. METHODS: Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. RESULTS: Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in SALL1, EYA1, RET, HNF1B, DSTYK, WNT4, and SIX5. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in DSTYK. CONCLUSION: A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations.