OBJECTIVE: To explore the clinical features and genomic abnorm ality of a fetus enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation. METHODS: The fetuse was found to have multicystic dysplastic kidneys with oligohydramnios upon ultrasonography during the second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA, chromosomal microarray analysis (CMA) and whole exome sequencing (WES). Sanger sequencing was used to verify the suspected variants in the family. RESULTS: Antenatal ultrasound examination at 19 weeks showed "polycystic" kidneys with Oligohydramnios. Delivery was by induced labour because of the critically low amniotic fluid volume. Testing of CMA was normal. WES showed a compound heterozygous mutation of c.1817G>A, p.W606X; c.432dupA, p.E145Rfs*18 mutations are novel mutations in this study. CONCLUSION The research may further expand the NPHP3 gene mutation spectrum. Enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation at least include one or two splice site mutation, frameshift mutation or nonsense mutation foetal poor prognosis.
Amniotic Fluid ; Female ; Humans ; Kidney Diseases, Cystic ; Multicystic Dysplastic Kidney/genetics* ; Mutation ; Oligohydramnios/genetics* ; Polycystic Kidney Diseases ; Pregnancy ; Ultrasonography, Prenatal

The primary cilium of renal epithelia acts as a transducer of extracellular stimuli. Polycystin (PC)1 is the protein encoded by the PKD1 gene that is responsible for the most common and severe form of autosomal dominant polycystic kidney disease (ADPKD). PC1 forms a complex with PC2 via their respective carboxy-terminal tails. Both proteins are expressed in the primary cilia. Mutations in either gene affect the normal architecture of renal tubules, giving rise to ADPKD. PC1 has been proposed as a receptor that modulates calcium signals via the PC2 channel protein. The effect of PC1 dosage has been described as the rate-limiting modulator of cystic disease. Reduced levels of PC1 or disruption of the balance in PC1/PC2 level can lead to the clinical features of ADPKD, without complete inactivation. Recent data show that ADPKD resulting from inactivation of polycystins can be markedly slowed if structurally intact cilia are also disrupted at the same time. Despite the fact that no single model or mechanism from these has been able to describe exclusively the pathogenesis of cystic kidney disease, these findings suggest the existence of a novel cilia-dependent, cyst-promoting pathway that is normally repressed by polycystin function. The results enable us to rethink our current understanding of genetics and cilia signaling pathways of ADPKD.
Calcium ; Cilia* ; Genetics ; Kidney Diseases, Cystic ; Polycystic Kidney, Autosomal Dominant* ; Transducers ; TRPP Cation Channels*

The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IP₃R3) in renal cyst development in autosomal dominant polycystic kidney disease (ADPKD). 2-aminoethoxy-diphenyl borate (2-APB) and shRNA were used to suppress the expression of IP₃R3. The effect of IP₃R3 on cyst growth was investigated in Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney specific Pkd1 knockout (PKD) mouse model. The underlying mechanism of IP₃R3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IP₃R3 was significantly increased in the kidneys of PKD mice. Inhibiting IP₃R3 by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model. Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IP₃R3, which was accompanied by a subcellular redistribution process in which IP₃R3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IP₃R3 further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle. These results suggest that the expression and subcellular distribution of IP₃R3 are involved in promoting renal cyst development, which implies IP₃R3 as a potential therapeutic target of ADPKD.
Animals ; Dogs ; Mice ; Cysts/genetics* ; Inositol 1,4,5-Trisphosphate Receptors/pharmacology* ; Kidney/metabolism* ; Polycystic Kidney Diseases/metabolism* ; Polycystic Kidney, Autosomal Dominant/drug therapy* ; Madin Darby Canine Kidney Cells

TRPP subfamily is an important member of transient receptor potential family. It has six transmembrane (TM) domains, a large extracellular loop between the first and second TM and 2-4 ankyrin repeats in the N terminal. TRPP subfamily includes TRPP2, TRPP3, TRPP5 etc. There are several differences in their structure, activation mode and function. TRPP subfamily is involved in many physiological mechanisms and its abnormal structure can lead to the formation of polycystic kidney. This subfamily is also closely related to gustation. In this review, we summarize recent research findings of TRPP subfamily and its association with polycystic kidney diseases.
Humans ; Polycystic Kidney Diseases ; genetics ; metabolism ; TRPP Cation Channels ; chemistry ; genetics ; physiology

OBJECTIVETo detect gene mutation in the patients with autosomal dominant polycystic kidney disease (PKD).

METHODSPolymerase chain reaction (PCR)-denaturing high-performance liquid chromatography (DHPLC) analyses were performed in 3o single copy region of PKD 1 gene (PKD1). DNA sequencing were carried out on PCR products with abnormal peak shape afterwards.

RESULTSA new nonsense mutation (C11901A in exon 42 of PKD1 was identified to cause serine in position 3897 turning to a stop codon. A missense mutation, C10737T, was detected in exon 35 which caused threonine in position 3509 turn to methionine. Two kinds of samesense mutation, G11824A and C11860T in exon 42, were found in normal control.

CONCLUSIONPKD1 mutation were detected successfully by PCR-DHPLC. A new nonsense mutation, a missense mutation and two polymorphisms are identified in this study.

Adult ; Codon, Nonsense ; Female ; Humans ; Male ; Mutation, Missense ; Polycystic Kidney Diseases ; genetics ; Polycystic Kidney, Autosomal Dominant ; genetics ; TRPP Cation Channels ; genetics ; Young Adult

OBJECTIVETo investigate clinical features and genetic mutations of a family affected with spinocerebellar ataxia 3 and polycystic kidney disease.

METHODSPolymerase chain reaction and DNA sequencing were employed to analyze exon 10 of the SCA3 gene, in addition with all exons and flanking sequences of PKD1 and PKD2 genes. The clinical features were also carefully analyzed.

RESULTSThe numbers of CAG repeat in the proband's SCA3 gene were 28/76, with the number of repeats in the mutant allele being in the full range. The sequence of exon 23 of the PKD1 gene was also found to be abnormal. Clinical symptoms of the proband were very serious, which were characterized by obvious ataxia, pyramidal signs, Meige syndrome, depression and high blood pressure.

CONCLUSIONHereditary spinocerebellar ataxia 3 and autonomic dominant polycystic kidney disease may co-occur, and genetic testing is the primary means of diagnosis.

Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Polycystic Kidney Diseases ; genetics ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Spinocerebellar Ataxias ; genetics

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a Chinese couple whom had conceived two fetuses featuring multiple malformations including polycystic kidney, polydactyly and encephalocele. METHODS: Following elective abortion, the fetus from the second pregnancy was subjected to whole exome sequencing. Suspected pathogenic variants were verified by Sanger sequencing of the fetus and its parents. RESULTS: The fetus was found to harbor compound heterozygous variants of the CEP290 gene, namely c.2743G>T (p.E915X) and c.2587-2A>T, which were respectively inherited from its father and mother. The same variants were not detected among 100 healthy controls nor reported previously. Bioinformatic analysis suggested both variants to be deleterious. The fetus was diagnosed with Meckel-Gruber syndrome. Prenatal diagnosis for the couple during their next pregnancy suggested that the fetus did not carry the above pathogenic variants. CONCLUSION The compound heterozygous variants of the CEP290 gene probably underlay the pathogenesis of Meckel-Gruber syndrome in the second fetus. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the couple, and also enriched the mutational spectrum of the CEP290 gene.
China ; Ciliary Motility Disorders ; Encephalocele/genetics* ; Female ; Genetic Testing ; Humans ; Pedigree ; Polycystic Kidney Diseases/genetics* ; Pregnancy ; Prenatal Diagnosis ; Retinitis Pigmentosa

To study the expression of beta-human chorionic gonadotropin (beta hCG) genes in renal cell carcinomas (RCC) and benign renal disease tissues, nested reverse transcription-polymerase chain reaction (RT-PCR) and restriction endonuclease analysis were employed to detect the expression of beta hCG genes in 44 cases of RCC tissues and 24 cases of benign renal disease tissues. It was found that 52% RCC samples revealed positive for beta hCG mRNA expression. Positive rate in advanced stage and poorly differentiated RCC was higher, but there was no significant difference. The positive rate of beta hCG mRNA expression was 54% in 24 cases of benign renal tissues, including 3 cases out of 6 polycystic kidneys, 7 cases out of 13 renal atrophies, 2 cases out of 2 oncocytomas and 1 case out of 2 pyonephrotic kidneys. beta 7 was most frequently transcribed subtype gene independent on the histology. These findings suggested beta hCG gene transcription is not only involved in RCC but also in benign renal diseases.
Adult ; Biomarkers, Tumor ; Carcinoma, Renal Cell ; genetics ; metabolism ; Chorionic Gonadotropin, beta Subunit, Human ; biosynthesis ; genetics ; Humans ; Kidney ; metabolism ; Kidney Diseases ; genetics ; metabolism ; Kidney Neoplasms ; genetics ; metabolism ; Polycystic Kidney Diseases ; metabolism ; RNA, Messenger ; biosynthesis ; genetics ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVETo investigate the polymorphisms of four microsatellites, D4S1534, D4S1563, D4S423 and D4S414, which are tightly linked to polycystic kidney disease 2 (PKD2) gene, and hence to provide a basis for studying the heterogeneity of adult polycystic kidney disease (APKD).

METHODSAn analysis on the DNA of some unrelated Chinese people was performed using polymerase chain reaction (PCR), polyacrylamide gel electrophoresis (PAGE) and silver staining.

RESULTSIn Chinese Hans, there are 11 alleles of D4S1534, and their sizes are 142-162 bp 14 alleles of D4S1563, 205-235 bp 17 alleles of D4S423, 103-135 bp; and 15 alleles of D4S414, 236-264 bp. The polymorphism information contents of the four microsatellites are 0.872, 0.844, 0.921 and 0.871 respectively.

CONCLUSIONIn the Chinese Han people studied above, the four microsatellite markers that have many alleles are highly polymorphic genetic markers and may serve as the data of population genetics, suggesting that all four microsatellites could be used in studies on heterogeneity of APKD, linkage analysis of APKD and forensic personal identification.

Alleles ; Asian Continental Ancestry Group ; genetics ; Genetic Linkage ; Genetic Predisposition to Disease ; Humans ; Membrane Proteins ; genetics ; Microsatellite Repeats ; genetics ; Polycystic Kidney Diseases ; genetics ; Polymorphism, Genetic ; TRPP Cation Channels

Adolescent ; Child ; Child, Preschool ; DNA Mutational Analysis ; Diagnosis, Differential ; Humans ; Infant ; Infant, Newborn ; Liver Diseases ; diagnosis ; genetics ; pathology ; Lung Diseases ; diagnosis ; genetics ; pathology ; Magnetic Resonance Imaging ; Mutation ; Polycystic Kidney, Autosomal Dominant ; diagnosis ; genetics ; pathology ; Polycystic Kidney, Autosomal Recessive ; diagnosis ; genetics ; pathology ; Prenatal Diagnosis ; Receptors, Cell Surface ; genetics ; Tomography, X-Ray Computed