Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Anciano , Estudios Retrospectivos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factor de Transcripción PAX8/metabolismo , Factor de Transcripción PAX8/genética , Factor de Transcripción PAX2/metabolismo , Factor de Transcripción PAX2/genética , Racemasas y Epimerasas/metabolismo , Racemasas y Epimerasas/genética , Nefrectomía , Estudios de SeguimientoRESUMEN
Clear cell renal cell carcinoma (ccRCC) is a lethal malignancy with high metastatic probability. Paired box 2 gene product (PAX2) carbonic anhydrase IX were biomolecules closely linked with ccRCC development and outcomes of multiple malignancies. We aim to explore the role of immunohistochemical staining of PAX2 and CAIX to predict ccRCC prognosis after nephrectomy. Surgical specimens of patients who were pathologically diagnosed as ccRCC were reviewed. Expression levels of PAX2 and CAIX were assessed via immunohistochemical staining. Recurrence-free survival (RFS) and overall survival were compared among different phenotypes. Inverse probability of treatment weighting (IPTW) was used for adjustment of confounding factors. 56 patients were included. Patients with PAX2 and CAIX high-expression (the two-high group, n=8) had significantly longer RFS and OS than those of simultaneously down-expression (the two-low group, n=31). Median RFS was 38.4 (95% CI: 32.3-NA) for the two-high group and 14.8 (95% CI: 13.4-39.0) months for the two-low group (P=0.043). IPTW confirmed PAX2 and CAIX co-expression is associated with less recurrence risk HR: 0.39, 95% CI: 0.17-0.92, P=0.031). Co-expression of PAX2 and CAIX is associated better prognosis of ccRCC. We are looking for validation by large cohort studies.
Asunto(s)
Anhidrasa Carbónica IX , Carcinoma de Células Renales , Inmunohistoquímica , Neoplasias Renales , Nefrectomía , Factor de Transcripción PAX2 , Humanos , Factor de Transcripción PAX2/metabolismo , Factor de Transcripción PAX2/genética , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/genética , Masculino , Femenino , Anhidrasa Carbónica IX/metabolismo , Anhidrasa Carbónica IX/genética , Nefrectomía/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/genética , Pronóstico , Anciano , Supervivencia sin Enfermedad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Adulto , Antígenos de NeoplasiasRESUMEN
Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.
Asunto(s)
Secuenciación del Exoma , Anomalías del Ojo , Factor de Transcripción PAX2 , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Humanos , Masculino , Femenino , Niño , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Factor de Transcripción PAX2/genética , Preescolar , Anomalías del Ojo/genética , Lactante , Mutación , Adolescente , Predisposición Genética a la EnfermedadRESUMEN
Renal cell carcinoma (RCC) is a significant oncological challenge due to its heterogeneous nature and limited treatment options. The PAX developmental gene family encodes nine highly conserved transcription factors that play crucial roles in embryonic development and organogenesis, which have been implicated in the occurrence and development of RCC. This review explores the molecular landscape of RCC, with a specific focus on the role of the PAX gene family in RCC tumorigenesis and disease progression. Of the various RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most prevalent, characterized by the loss of the von Hippel-Lindau (VHL) tumor suppressor gene. Here, we review the published literature on the expression patterns and functional implications of PAX genes, particularly PAX2 and PAX8, in the three most common RCC subtypes, including ccRCC, papillary RCC (PRCC), and chromophobe RCC (ChRCC). Further, we review the interactions and potential biological mechanisms involving PAX genes and VHL loss in driving the pathogenesis of RCC, including the key signaling pathways mediated by VHL in ccRCC and associated mechanisms implicating PAX. Lastly, concurrent with our update regarding PAX gene research in RCC, we review and comment on the targeting of PAX towards the development of novel RCC therapies.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Factores de Transcripción Paired Box , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Factores de Transcripción Paired Box/genética , Factores de Transcripción Paired Box/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Factor de Transcripción PAX8/genética , Factor de Transcripción PAX8/metabolismo , Transducción de Señal/genéticaRESUMEN
PAX2 regulates kidney development, and its expression persists in parietal epithelial cells (PECs), potentially serving as a podocyte reserve. We hypothesized that mice with a Pax2 pathogenic missense variant (Pax2A220G/+) have impaired PEC-mediated podocyte regeneration. Embryonic wild-type mouse kidneys showed overlapping expression of PAX2/Wilms' tumor-1 (WT-1) until PEC and podocyte differentiation, reflecting a close lineage relationship. Embryonic and adult Pax2A220G/+ mice have reduced nephron number but demonstrated no glomerular disease under baseline conditions. Pax2A220G/+ mice compared with wild-type mice were more susceptible to glomerular disease after adriamycin (ADR)-induced podocyte injury, as demonstrated by worsened glomerular scarring, increased podocyte foot process effacement, and podocyte loss. There was a decrease in PAX2-expressing PECs in wild-type mice after adriamycin injury accompanied by the occurrence of PAX2/WT-1-coexpressing glomerular tuft cells. In contrast, Pax2A220G/+ mice showed no changes in the numbers of PAX2-expressing PECs after adriamycin injury, associated with fewer PAX2/WT-1-coexpressing glomerular tuft cells compared with injured wild-type mice. A subset of PAX2-expressing glomerular tuft cells after adriamycin injury was increased in Pax2A220G/+ mice, suggesting a pathological process given the worse outcomes observed in this group. Finally, Pax2A220G/+ mice have increased numbers of glomerular tuft cells expressing Ki-67 and cleaved caspase-3 compared with wild-type mice after adriamycin injury, consistent with maladaptive responses to podocyte loss. Collectively, our results suggest that decreased glomerular numbers in Pax2A220G/+ mice are likely compounded with the inability of their mutated PECs to regenerate podocyte loss, and together these two mechanisms drive the worsened focal segmental glomerular sclerosis phenotype in these mice.NEW & NOTEWORTHY Congenital anomalies of the kidney and urinary tract comprise some of the leading causes of kidney failure in children, but our previous study showed that one of its genetic causes, PAX2, is also associated with adult-onset focal segmental glomerular sclerosis. Using a clinically relevant model, our present study demonstrated that after podocyte injury, parietal epithelial cells expressing PAX2 are deployed into the glomerular tuft to assist in repair in wild-type mice, but this mechanism is impaired in Pax2A220G/+ mice.
Asunto(s)
Doxorrubicina , Glomérulos Renales , Mutación Missense , Factor de Transcripción PAX2 , Podocitos , Animales , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismo , Podocitos/metabolismo , Podocitos/patología , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Doxorrubicina/toxicidad , Ratones , Regeneración , Modelos Animales de Enfermedad , Proliferación Celular , Ratones Endogámicos C57BL , Fenotipo , Apoptosis , Masculino , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/inducido químicamenteRESUMEN
Renal coloboma syndrome (RCS) and dominant optic atrophy are mainly caused by heterozygous mutations in PAX2 and OPA1, respectively. We describe a patient with digenic mutations in PAX2 and OPA1. A female infant was born without perinatal abnormalities. Magnetic resonance imaging at 4 months of age showed bilateral microphthalmia and optic nerve hypoplasia. Appropriate body size was present at 2 years of age, and mental development was favorable. Color fundus photography revealed severe retinal atrophy in both eyes. Electroretinography showed slight responses in the right eye, but no responses in the left eye, suggesting a high risk of blindness. Urinalysis results were normal, creatinine-based estimated glomerular filtration rate was 63.5 mL/min/1.73 m2, and ultrasonography showed bilateral hypoplastic kidneys. Whole exome sequencing revealed de novo frameshift mutations in PAX2 and OPA1. Both variants were classified as pathogenic (PVS1, PS2, PM2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Genetic testing for ocular diseases should be considered for patients with suspected RCS and a high risk of total blindness.
Asunto(s)
Coloboma , GTP Fosfohidrolasas , Factor de Transcripción PAX2 , Reflujo Vesicoureteral , Humanos , Femenino , Factor de Transcripción PAX2/genética , GTP Fosfohidrolasas/genética , Coloboma/genética , Coloboma/diagnóstico , Reflujo Vesicoureteral/genética , Reflujo Vesicoureteral/diagnóstico , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/diagnóstico , Anomalías Urogenitales/genética , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/complicaciones , Mutación del Sistema de Lectura , Secuenciación del Exoma , Lactante , Preescolar , Mutación , Insuficiencia RenalRESUMEN
Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo. Pyrosequencing and the demethylating drug 5-Aza-dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland.
Asunto(s)
Carcinoma Endometrioide , Hiperplasia Endometrial , Neoplasias Endometriales , Humanos , Femenino , Animales , Ratones , Carcinoma Endometrioide/patología , Neoplasias Endometriales/patología , Progesterona/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Metilación , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Estrógenos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismoRESUMEN
INTRODUCTION: Restricted repetitive behaviors (RRBs), which are associated with many different neurological and mental disorders, such as obsessive-compulsive disorder (OCD) and autism, are patterns of behavior with little variation and little obvious function. Paired Box 2 (Pax2) is a transcription factor that is expressed in many systems, including the kidney and the central nervous system. The protein that is encoded by Pax2 has been implicated in the development of the nervous system and neurodevelopmental disorders. In our previous study, Pax2 heterozygous gene knockout mice (Pax2+/- mice) showed abnormally increased self-grooming and impaired learning and memory abilities. However, it remains unclear which cell type is involved in this process. In this study, we deleted Pax2 only in the nervous system to determine the regulatory mechanism of Pax2 in RRBs. METHODS: In this study, Pax2 nervous system-specific knockout mice (Nestin-Pax2 mice) aged 6-8 weeks and Pax2 flox mice of the same age were recruited as the experimental group. Tamoxifen and vehicle were administered via intraperitoneal injection to induce Pax2 knockout after gene identification. Western blotting was used to detect Pax2 expression. After that, we assessed the general health of these two groups of mice. The self-grooming test, marble burying test and T-maze acquisition and reversal learning test were used to observe the lower-order and higher-order RRBs. The three-chamber test, Y-maze, and elevated plus-maze were used to assess social ability, spatial memory ability, and anxiety. Neural circuitry tracing and transcriptome sequencing (RNA-seq) were used to observe the abnormal neural circuitry, differentially expressed genes (DEGs) and signaling pathways affected by Pax2 gene knockout in the nervous system and the putative molecular mechanism. RESULTS: (1) The Nestin-Pax2 mouse model was successfully constructed, and the Nestin-Pax2 mice showed decreased expression of Pax2. (2) Nestin-Pax2 mice showed increased self-grooming behavior and impaired T-maze reversal behavior compared with Pax2 flox mice. (3) An increased number of projection fibers can be found in the mPFC projecting to the CA1 and BLA, and a reduction in IGFBP2 can be found in the hippocampus of Nestin-Pax2 mice. CONCLUSION: The results demonstrated that loss of Pax2 in the nervous system leads to restricted repetitive behaviors. The mechanism may be associated with impaired neural circuitry and a reduction in IGFBP2.
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Cognición , Sistema Nervioso , Humanos , Ratones , Animales , Ratones Noqueados , Nestina , Hipocampo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Factor de Transcripción PAX2/genéticaRESUMEN
Acute kidney injury (AKI) is a common condition that lacks effective treatments. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that control pathogenesis and recovery. Identifying the molecular and genetic regulators unique to nephron segments that dictate vulnerability to injury and regenerative potential could lead to new therapeutic targets to treat ischemic kidney injury. Pax2 and Pax8 are homologous transcription factors with overlapping functions that are critical for kidney development and are re-activated in AKI. Here, we examined the role of Pax2 and Pax8 in recovery from ischemic AKI and found them upregulated after severe AKI and correlated with chronic injury. Surprisingly, proximal-tubule-selective deletion of Pax2 and Pax8 resulted in a less severe chronic injury phenotype. This effect was mediated by protection against the acute insult, similar to pre-conditioning. Prior to injury, Pax2 and Pax8 mutant mice develop a unique subpopulation of proximal tubule cells in the S3 segment that displayed features usually seen only in acute or chronic injury. The expression signature of these cells was strongly enriched with genes associated with other mechanisms of protection against ischemic AKI including caloric restriction, hypoxic pre-conditioning, and female sex. Thus, our results identified a novel role for Pax2 and Pax8 in mature proximal tubules that regulates critical genes and pathways involved in both the injury response and protection from ischemic AKI.
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Lesión Renal Aguda , Túbulos Renales Proximales , Factor de Transcripción PAX2 , Factor de Transcripción PAX8 , Insuficiencia Renal Crónica , Animales , Femenino , Ratones , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/genética , Isquemia/complicaciones , Túbulos Renales Proximales/patología , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/genética , Daño por Reperfusión/genética , Factor de Transcripción PAX8/genética , Factor de Transcripción PAX8/metabolismo , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismoRESUMEN
Focal segmental glomerulosclerosis 7 (FSGS7, # 616002) is a condition marked by significant proteinuria with or without features of nephrotic syndrome. Heterozygous mutations in the PAX2 gene on chromosome 10q24 can cause FSGS7. Here, we generated an induced pluripotent stem cell line SDQLCHi062-A from a thirteen -years-old boy with FSGS7 caused by heterozygous mutation (c.226 G>A, p.G76S) in the PAX2 gene (OMIM * 167409). The established iPSC line was validated by pluripotency markers expression, original gene mutation and demonstrated trilineage differentiation potential in vitro.
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Células Madre Pluripotentes Inducidas , Síndrome Nefrótico , Masculino , Humanos , Adolescente , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Diferenciación Celular/genética , Heterocigoto , Factor de Transcripción PAX2/genéticaRESUMEN
The PAX2 gene is a transcription factor that is essential for the development of the urinary system among other transcription factors. The role of PAX2 is highlighted from the seventh week of gestation, when it is involved in development processes and the emergence of nephrons and collecting tubes. Being an important factor in renal development, mutations of this gene can produce severe alterations in the development of the urinary tract, namely congenital anomalies of the kidneys and urinary tract. The first reported cases described with the PAX2 mutation included both renal anomalies and the involvement of other organs, such as the eyes, producing renal coloboma syndrome. Over the years, numerous cases have been reported, including those with only renal and urinary tract anomalies. The aim of this review is to present a summary of pediatric patients described to have mutations in the PAX2 gene to contribute to a better understanding of the genetic mechanism causing anomalies of the kidneys and urinary tract. In this review, we have included only pediatric cases with renal and urinary tract disorders, without the involvement of other organs. From what we know so far from the literature, this is the first review gathering pediatric patients presenting the PAX2 mutation who have been diagnosed exclusively with renal and urinary tract disorders.
Asunto(s)
Enfermedades Renales , Factor de Transcripción PAX2 , Insuficiencia Renal , Niño , Humanos , Riñón , Enfermedades Renales/genética , Mutación , Nefronas , Factor de Transcripción PAX2/genética , Factores de TranscripciónRESUMEN
OBJECTIVE: To evaluate the contribution of PAX2, ARID1A, and FOXA1 biomarkers to diagnosis in cases with atypical endometrial hyperplasia (AEH). STUDY DESIGN: Descriptive Study. Place and Duration of the Study: Pathology Department of Umraniye Training and Research Hospital, from January 2018 to December 2020. METHODOLOGY: Curettage materials of 100 patients diagnosed with AEH which stained PAX2, ARID1A, and FOXA1, were evaluated. The staining patterns in the atypical endometrial glandular areas were grouped as slight-no loss, moderate loss, and complete loss / severe loss for all three biomarkers. Complete or/severe loss in AEH was considered helpful in the diagnosis. RESULTS: Complete loss / severe loss rates in curettages were 84% for PAX2, 5% for ARID1A, and 15% for FOXA1, respectively. When used in combination, complete loss / severe loss rates were 85% in at least one of the three markers, 84% in PAX2 and/or ARID1A, 85% in PAX2 and/or FOXA1, and 17% in ARID1A and/or FOXA1. CONCLUSION: Although all 3 biomarkers showed marked staining loss, PAX2 is the most sensitive biomarker for the diagnosis of AEH in curettage materials. KEY WORDS: Endometrium, Atypical hyperplasia, PAX2, ARID1A, FOXA1.
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Hiperplasia Endometrial , Neoplasias Endometriales , Lesiones Precancerosas , Femenino , Humanos , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/patología , Neoplasias Endometriales/patología , Endometrio/patología , Biomarcadores , Lesiones Precancerosas/patología , Proteínas de Unión al ADN , Factores de Transcripción , Factor de Transcripción PAX2/genética , Factor Nuclear 3-alfa del Hepatocito/genéticaRESUMEN
OBJECTIVE: To explore the genetic basis of a Chinese pedigree affected with chronic kidney disease (CKD). METHODS: A Chinese pedigree comprised of 10 individuals from four generation who had visited the First Affiliated Hospital of Dali University from August 15, 2018 to July 5, 2021 was selected as the study subject. Clinical data of the proband were collected, and a pedigree survey was conducted. The proband was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The proband, a 41-year-old female, has been diagnosed with chronic nephritis for more than 4 years. Routine urinary examination showed proteinuria and blood creatinine of 1 130 µmol/L. Renal biopsy has revealed hyperplastic glomerulonephritis, moderate tubulointerstitial disease and renal arteriosclerosis. Her elder sister, younger brother, younger sister and mother were all diagnosed with CKD stage 5. Except for her elder sister, all of them had deceased, whilst no abnormality was found in the remainders. Genetic testing revealed that the proband and four family members had harbored a c.467G>A missense variant of the PAX2 gene. The variant has been associated with focal segmental glomerulosclerosis and classified as likely pathogenic (PS1+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). CONCLUSION: The c.167Gï¼A variant of the PAX2 gene probably underlay the CKD in this Chinese pedigree.
Asunto(s)
Factor de Transcripción PAX2 , Insuficiencia Renal Crónica , Adulto , Femenino , Humanos , Masculino , Pueblos del Este de Asia , Pruebas Genéticas , Mutación , Factor de Transcripción PAX2/genética , Linaje , Insuficiencia Renal Crónica/genéticaRESUMEN
Renal cell carcinoma (RCC) is the most common form of kidney cancer, consisting of multiple distinct subtypes. RCC has the highest mortality rate amongst the urogenital cancers, with kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and kidney chromophobe carcinoma (KICH) being the most common subtypes. The Paired-box (PAX) gene family encodes transcription factors, which orchestrate multiple processes in cell lineage determination during embryonic development and organogenesis. Several PAX genes have been shown to be expressed in RCC following its onset and progression. Here, we performed real-time quantitative polymerase chain reaction (RT-qPCR) analysis on a series of human RCC cell lines, revealing significant co-expression of PAX2, PAX6, and PAX8. Knockdown of PAX2 or PAX8 mRNA expression using RNA interference (RNAi) in the A498 RCC cell line resulted in inhibition of cell proliferation, which aligns with our previous research, although no reduction in cell proliferation was observed using a PAX2 small interfering RNA (siRNA). We downloaded publicly available RNA-sequencing data and clinical histories of RCC patients from The Cancer Genome Atlas (TCGA) database. Based on the expression levels of PAX2, PAX6, and PAX8, RCC patients were categorized into two PAX expression subtypes, PAXClusterA and PAXClusterB, exhibiting significant differences in clinical characteristics. We found that the PAXClusterA expression subgroup was associated with favorable clinical outcomes and better overall survival. These findings provide novel insights into the association between PAX gene expression levels and clinical outcomes in RCC patients, potentially contributing to improved treatment strategies for RCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismo , Neoplasias Renales/metabolismo , Riñón/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: The vertebrate inner ear contains distinct sensory epithelia specialized for auditory or vestibular function. In zebrafish, the first sensory epithelia form at opposite ends of the otic vesicle and are functionally distinct: the anterior utricular macula is essential for vestibular function whereas the posterior saccular macula is critical for hearing. Mechanisms distinguishing these maculae are not clear. Here, we examined the effects of manipulating Fgf or Hh on expression of pax5 and pou3f3b, unique markers of utricular and saccular identity. We also examined the roles of pax2a and atoh1a/b, early regulators of sensory specification. RESULTS: fgf3 and fgf8a were uniquely required for pax5 and pou3f3b, respectively. Elevating Fgf or blocking Hh expanded expression of pax5 but repressed pou3f3b, while blocking Fgf had the opposite effect. Blocking sensory specification did not affect pax5 or pou3f3b, but both markers were lost in pax2a-/- mutants. Maintenance of pax2a expression requires Fgf, Hh and Pax2a itself. CONCLUSION: Specification of utricular identity requires high Fgf and is repressed by Hh, whereas saccular identity requires Hh plus low Fgf. pax2a acts downstream of Fgf and Hh to maintain both fates. Comparison with mouse suggests this may reflect a broadly conserved developmental mechanism.
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Oído Interno , Pez Cebra , Animales , Ratones , Oído Interno/metabolismo , Audición , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismo , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Factor 1 de Crecimiento de Fibroblastos , Proteínas Hedgehog , Factores de Crecimiento de FibroblastosRESUMEN
PAX2 is a transcription factor expressed during embryogenesis in the eye, ear, CNS, and genitourinary tract, and is one of the major regulators of kidney development. Mutations in this gene are associated with papillorenal syndrome (PAPRS), a genetic condition characterized by optic nerve dysplasia and renal hypo/dysplasia. In the last 28 years, many cohort studies and case reports highlighted PAX2's involvement in a large spectrum of kidney malformations and diseases, with or without eye abnormalities, defining the phenotypes associated with PAX2 variants as "PAX2-related disorders". Here, we reported two new sequence variations and reviewed PAX2 mutations annotated on the Leiden Open Variation Database 3.0. DNA was extracted from the peripheral blood of 53 pediatric patients with congenital abnormalities of the kidney and urinary tract (CAKUT). PAX2 gene-coding exonic and flanking intronic regions were sequenced with Sanger technology. Two unrelated patients and two twins carrying one known and two unknown PAX2 variations were observed. The frequency of PAX2-related disorders in this cohort was 5.8%, considering all CAKUT phenotypes (16.7% in the PAPRS phenotype and 2.5% in non-syndromic CAKUT). Although PAX2 mutations have a higher frequency in patients with PAPRS or non-syndromic renal hypoplasia, from the review of variants reported to date in LOVD3, PAX2-related disorders are detected in pediatric patients with other CAKUT phenotypes. In our study, only one patient had a CAKUT without an ocular phenotype, but his twin had both renal and ocular involvement, confirming the extreme inter- and intrafamilial phenotypic variability.
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Enfermedades Renales , Factor de Transcripción PAX2 , Sistema Urinario , Reflujo Vesicoureteral , Humanos , Riñón/anomalías , Enfermedades Renales/genética , Mutación , Factor de Transcripción PAX2/genética , Fenotipo , Reflujo Vesicoureteral/genéticaRESUMEN
Renal coloboma syndrome (RCS) is a disease characterized by kidney and ocular anomalies (kidney hypodysplasia and coloboma). RCS is caused, in half of the cases, by mutations in the paired box 2 (PAX2) gene, a critical organogenesis transcriptional factor. We report the case of a newborn with kidney hypodysplasia in a negative parental context where mother and father were phenotypically unaffected at the initial evaluation. The maternal family presented an important history of kidney disease with undefined diagnosis. Molecular characterization identified a PAX2 variant, classified as likely pathogenic. This variant segregates with the disease, and it was also found in the newborn, explaining his severe symptoms. It is noteworthy that the mother shows the same PAX2 variant, with an apparently negative kidney phenotype, displaying the possibility of an extreme variable expressivity of the disease. This feature suggests extreme caution in segregation analysis and family counseling of PAX2 pedigrees.
Asunto(s)
Coloboma , Insuficiencia Renal , Reflujo Vesicoureteral , Humanos , Coloboma/genética , Coloboma/diagnóstico , Coloboma/patología , Reflujo Vesicoureteral/genética , Reflujo Vesicoureteral/diagnóstico , Reflujo Vesicoureteral/patología , Riñón/patología , Mutación , Variación Biológica Poblacional , Factor de Transcripción PAX2/genéticaRESUMEN
OBJECTIVE@#To explore the genetic basis of a Chinese pedigree affected with chronic kidney disease (CKD).@*METHODS@#A Chinese pedigree comprised of 10 individuals from four generation who had visited the First Affiliated Hospital of Dali University from August 15, 2018 to July 5, 2021 was selected as the study subject. Clinical data of the proband were collected, and a pedigree survey was conducted. The proband was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The proband, a 41-year-old female, has been diagnosed with chronic nephritis for more than 4 years. Routine urinary examination showed proteinuria and blood creatinine of 1 130 μmol/L. Renal biopsy has revealed hyperplastic glomerulonephritis, moderate tubulointerstitial disease and renal arteriosclerosis. Her elder sister, younger brother, younger sister and mother were all diagnosed with CKD stage 5. Except for her elder sister, all of them had deceased, whilst no abnormality was found in the remainders. Genetic testing revealed that the proband and four family members had harbored a c.467G>A missense variant of the PAX2 gene. The variant has been associated with focal segmental glomerulosclerosis and classified as likely pathogenic (PS1+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The c.167G>A variant of the PAX2 gene probably underlay the CKD in this Chinese pedigree.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Pueblos del Este de Asia , Pruebas Genéticas , Mutación , Factor de Transcripción PAX2/genética , Linaje , Insuficiencia Renal Crónica/genéticaRESUMEN
In zebrafish, sensory epithelia and neuroblasts of the inner ear form simultaneously in abutting medial and lateral domains, respectively, in the floor of the otic vesicle. Previous studies support regulatory roles for Fgf and Wnt, but how signaling is coordinated is poorly understood. We investigated this problem using pharmacological and transgenic methods to alter Fgf or Wnt signaling from early placodal stages to evaluate later changes in growth and patterning. Blocking Fgf at any stage reduces proliferation of otic tissue and terminates both sensory and neural specification. Wnt promotes proliferation in the otic vesicle but is not required for sensory or neural development. However, sustained overactivation of Wnt laterally expands sensory epithelia and blocks neurogenesis. pax2a, sp5a and sp5l are coregulated by Fgf and Wnt and show overlapping expression in the otic placode and vesicle. Gain- and loss-of-function studies show that these genes are together required for Wnt's suppression of neurogenesis, as well as some aspects of sensory development. Thus, pax2a, sp5a and sp5l are critical for mediating Fgf and Wnt signaling to promote spatially localized sensory and neural development.