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

OBJECTIVES: To study the clinical and genetic features of Joubert syndrome (JS) in children. METHODS: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022. RESULTS: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes. CONCLUSIONS For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.
Male ; Female ; Humans ; Child ; Cerebellum ; Abnormalities, Multiple/genetics* ; Kidney Diseases, Cystic/genetics* ; Eye Abnormalities/genetics* ; Retina ; Retrospective Studies ; Muscle Hypotonia/genetics*

OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23⁺⁵ weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
Female ; Humans ; Pregnancy ; Pedigree ; Cerebellum/abnormalities* ; Abnormalities, Multiple/diagnosis* ; Eye Abnormalities/diagnosis* ; Kidney Diseases, Cystic/diagnosis* ; Phosphoric Monoester Hydrolases/genetics* ; Retina/abnormalities* ; East Asian People ; Mutation

OBJECTIVES: To improve the understanding of the clinical phenotypes and genetic characteristics of nephronophthisis (NPHP) and related syndromes in children. METHODS: A retrospective analysis was performed on the medical data of eight children with NPHP and related syndromes who were diagnosed and treated in the Department of Pediatrics of the Second Hospital of Hebei Medical University, from January 2018 to November 2022. The clinical characteristics and genetic testing results were analyzed. RESULTS: Among these eight children, there were five boys and three girls, with an age of onset ranging from 15 months to 12 years. All 8 children exhibited different degrees of renal function abnormalities when they attended the hospital. Among the eight children, two had the initial symptom of delayed development, two had the initial symptom of anemia, and two were found to have abnormal renal function during physical examination. The extrarenal manifestations included cardiovascular abnormalities in two children, skeletal dysplasia in two children, liver dysfunction in one child, retinitis pigmentosa in one child, and visceral translocation in one child. All eight children had renal structural changes on ultrasound, and four children had mild to moderate proteinuria based on routine urine test. Of all eight children, five had NPHP1 gene mutations and one each had a gene mutation in the NPHP3, IFT140, and TTC21B genes, and four new mutation sites were discovered. CONCLUSIONS Children with NPHP and related syndromes often have the initial symptom of delayed development or anemia, and some children also have extrarenal manifestations. NPHP and related syndromes should be considered for children with unexplained renal dysfunction, and high-throughput sequencing may help to make a confirmed diagnosis.
Child ; Humans ; Retrospective Studies ; Syndrome ; Kidney Diseases, Cystic/genetics* ; Mutation ; Phenotype

Humans ; Polycystic Kidney, Autosomal Recessive/genetics*

OBJECTIVE: To detect potential variants in eight Chinese pedigrees affected with autosomal dominant polycystic kidney disease (ADPKD) and provide prenatal diagnosis for two of them. METHODS: Whole exome sequencing and high-throughput sequencing were carried out to detect variants of PKD1 and PKD2 genes in the probands. Sanger sequencing was used to validate the variants, and their pathogenicity was predicted by searching the ADPKD and protein variation databases. RESULTS: Eight PKD1 variants were detected, which have included five nonsense mutations and three missense mutations. Among these, four nonsense variants (PKD1: c.7555C>T, c.7288C>T, c.4957C>T, c.11423G>A) were known to be pathogenic, whilst one missense variant (PKD1: c.2180T>G) was classified as likely pathogenic. Three novel variants were detected, which included c.6781G>T (p.Glu2261*), c.109T>G (p.Cys37Gly) and c.8495A>G (p.Asn2832Ser). Prenatal testing showed that the fetus of one family has carried the same mutation as the proband, while the fetus of another family did not. CONCLUSION PKD1 variants, including three novel variants, have been identified in the eight pedigrees affected with ADPKD. Based on these results, prenatal diagnosis and genetic counseling have been provided.
DNA Mutational Analysis/methods* ; Female ; Humans ; Mutation ; Pedigree ; Polycystic Kidney, Autosomal Dominant/genetics* ; Pregnancy ; Prenatal Diagnosis ; TRPP Cation Channels/genetics*

OBJECTIVE: To explore the clinical characteristics and molecular pathogenesis of a child with autosomal dominant polycystic kidney disease (ARPKD). METHODS: Prenatal ultrasound, clinical feature and family history of the child were analyzed. Whole exome sequencing was carried out for the child. Candidate variants were verified by Sanger sequencing. RESULTS: The child has featured premature birth with very low weight, neonatal respiratory distress, metabolic acidosis, and congenital nephrotic syndrome. Gene sequencing revealed that he has harbored compound heterozygous variants of the PKHD1 gene (NM_138694), including c.3885T>A (p.Tyr1295*) in exon 32 and c.7812_7816dupTGATA (p.Thr2606Metfs*63) in exon 49, which were respectively inherited from his mother and father. CONCLUSION The compound heterozygous variants of the PKHD1 gene probably underlay the disease in this child.
Child ; Exons ; Female ; Genetic Testing ; Humans ; Infant, Newborn ; Male ; Mutation ; Polycystic Kidney, Autosomal Recessive/genetics* ; Pregnancy ; Receptors, Cell Surface/genetics*

OBJECTIVE: To explore the genetic etiology of two fetuses with 17q12 microdeletion syndrome. METHODS: Chromosomal karyotype analysis, whole exome sequencing (WES) and chromosomal microarray analysis (CMA) were carried out for the fetuses. Relevant literature was searched in databases such as CNKI, Wanfang and PubMed to summarize the prenatal ultrasound finding, pregnancy outcome and clinical phenotype of the syndrome. RESULTS: Both fetuses were found have renal parenchymal echo enhancement, accompanied by presence of renal cysts or hydramnios. Both were found to have a normal chromosomal karyotype, but had a 17q12 microdeletion by WES and CMA analysis. A total of 433 cases of 17q12 microdeletion syndromes have been reported in the literature, with renal cysts and diabetes as the most common phenotypes. Among 240 fetuses diagnosed with this syndrome, 72.9% showed unilateral or bilateral renal parenchymal echo enhancement, and 23.3% showed unilateral or bilateral renal cysts. Among these, 68 had reported the pregnancy outcome, for which 70.5% of pregnant women had opted termination of the pregnancy. CONCLUSION WES and CMA can effectively detect 17q12 microdeletion. The clinical manifestations of this syndrome mainly include enhanced renal parenchymal echo, renal cyst, kidney disease and early-onset diabetes. Upon prenatal consultation, the prognosis of the fetus should be fully informed, and advice should be provided in combination with the preference of the couple, pregnancy history, family condition and other aspects.
Chromosome Disorders/diagnosis* ; Female ; Fetus ; Humans ; Karyotyping ; Kidney Diseases, Cystic ; Microarray Analysis ; Pregnancy ; Prenatal Diagnosis ; Syndrome

OBJECTIVE: To explore the genetic basis for a fetus featuring infantile polycystic kidney disease (IPKD). METHODS: Following elective abortion, fetal tissue and peripheral blood samples of its parents were collected for the extraction of genomic DNA. Whole exome sequencing was carried out to detect potential variants correlated with the phenotype. RESULTS: The fetus was found to harbor a heterozygous c.1370C>T (p.P457L) variant of the HNF1B gene, which was unreported previously. The same variant was not detected in either parent. CONCLUSION The heterozygous c.1370C>T (p.P457L) variant of the HNF1B gene probably underlay the IPKD in this fetus. Above finding has enabled genetic counseling and prenatal diagnosis for the family.
Female ; Fetus ; Hepatocyte Nuclear Factor 1-beta/genetics* ; Humans ; Mutation ; Phenotype ; Polycystic Kidney, Autosomal Recessive ; Pregnancy ; Prenatal Diagnosis ; Whole Exome Sequencing

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