Phenotypic spectrum and genetics of PAX2-related disorder in the Chinese cohort

Yang, Xue; Li, Yaqi; Ye, Fang; Shi, Hua; Xiang, Tianchao; Liu, Jiaojiao; Liu, Jialu; Tang, Xiaoshan; Fang, Xiaoyan; Chen, Jing; Zhai, Yi­hui; Shen, Qian; Bi, Yunli; Qian, Yanyan; Wu, Bingbing; Wang, Huijun; Zhou, Wenhao; Ma, Duan; Bai, Hao; Mao, Jianhua; Chen, Lizhi; Wang, Xiaowen; Gao, Xiaojie; Zhang, Ruifeng; Zhuang, Jieqiu; Zhang, Aihua; Jiang, Xiaoyun; Xu, Hong; Rao, Jia

doi:10.1186/s12920-021-01102-x

Cited by 8 publications

(14 citation statements)

References 24 publications

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“…Whether pyloric stricture is a part of the presentation of PAX2 mutation or it is a coincidence warrants further observation. We summarize the clinical presentations and mutation types from three recent studies, as listed in Table 2 (3,14,15). The median age at initial presentation is 8.2 years, and 41% of cases presented initially between 1 and 10 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…We summarize the clinical presentations and mutation types from three recent studies, as listed in Table 2 ( 3 , 14 , 15 ). The median age at initial presentation is 8.2 years, and 41% of cases presented initially between 1 and 10 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…Among previous studies, no clear genotype/phenotype correlation is observed, and neither the type nor the location of the mutation is predictive of clinical presentation or disease severity ( 2 , 6 ). However, a recent study has shown a trend that frameshift mutation is more likely to result in typical renal coloboma syndrome, and missense mutation is associated with nephrosis (pathological changes of FSGS without renal morphological abnormalities) ( 15 ). Despite this observation, a huge phenotypic heterogeneity is noticed among different patients with the same variants.…”

Section: Discussionmentioning

confidence: 99%

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PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

et al. 2022

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Paired box 2 (PAX2)-related disorder is an autosomal dominant genetic disorder associated with kidney and eye abnormalities and can result in end stage renal disease (ESRD). Despite reported low prevalence of PAX2 mutations, the prevalence of PAX2 related disorders may have been underestimated in past studies. With improved genetic sequencing techniques, more genetic abnormalities are being detected than ever before. Here, we report three patients from two families with PAX2 mutations identified within 1 year. Two patients were adults with chronic kidney disease and were followed for decades without correct diagnoses, including one with ESRD who had even undergone kidney transplant. The third patient was a neonate in whom PAX2-related disorder manifested as oligohydramnios, coloboma, and renal failure that progressed to ESRD within 1 year after birth. The phenotypes of PAX2 gene mutation were shown to be highly variable, even within the same family. Early detection promoted genetic counseling and guided clinical management. The appropriate time point for genetic study is an important issue. Clinicians must be more alert for PAX2 mutation when facing patients with congenital kidney and urinary tract anomalies, chronic kidney disease of unknown etiology, involvement of multiple systems, and/or a family history of renal disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

et al. 2022

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“…A surprising discordant finding was identification a pathogenic PAX2 variant with a patient diagnosed with IgA nephropathy on renal biopsy. Yang et al (2021) presented a cohort of 32 patients with PAX2 nephropathy, with one patient having renal biopsy findings compatible with IgA nephropathy. This might be explained by the rare presentation and phenotypic expansion of PAX2 ‐related kidney disease, which typically includes dysplasia (Chang et al, 2022; Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Genetic diagnosis and renal biopsy findings in the setting of a renal genetics clinic

Moshe

Bekheirnia

Smith

et al. 2022

American J of Med Genetics Pt C

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As genetic testing becomes more available, its utilization as an early diagnostic tool in nephrology is more common. The objective of the study is to examine diagnostic agreement between the renal biopsy findings and genetic diagnoses. A retrospective study was conducted in February 2022. A total of 28 patients had both genetic diagnosis and histologic results (n = 1 nephrectomy, n = 27 biopsy). We collected clinical, renal biopsy findings, and genetic information. The relationship between the histologic findings and the genetic diagnoses was classified as: concordant, nonspecific, and discordant. A total of 15 males and 13 females were included (mean age = 9.6 years). Clinical suspicion of Alport syndrome was the most common reason for referral (n = 11, 39.3%), followed by nephrotic syndrome (n = 8, 28.5%), "other" (n = 6, 21.4%), cystic kidney disease (n = 1, 3.6%), isolated hematuria (n = 1, 3.6%), and non-nephrotic proteinuria (n = 1, 3.6%). The overall concordance rate between renal histologic and genetic diagnoses was 71.4% (20/28), nonspecific biopsy results were observed in 17.9% (5/28), and discordant results were observed in 10.7%(3/28). All patients referred for suspected Alport Syndrome had pathogenic/likely

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“…Pax2 is expressed in distinct regions of the developing central nervous system, particularly in the developing forebrain, midbrain, and hindbrain during the early stages of embryogenesis and later in the midbrain–hindbrain boundary, diencephalon and cerebellum. Patients with Pax2 mutations exhibit various neurodevelopmental disorders, such as ASD, epilepsy, intellectual disability, and developmental delay 10,11 . In a previous study, we investigated the behavioral phenotype and possible underlying mechanism in Pax2 heterozygous gene knockout mice ( Pax2 +/− mice).…”

Section: Introductionmentioning

confidence: 99%

Impaired neural circuitry of hippocampus in Pax2 nervous system‐specific knockout mice leads to restricted repetitive behaviors

Wang,

Tang

et al. 2023

CNS Neurosci Ther

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IntroductionRestricted 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.MethodsIn 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.ConclusionThe 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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Phenotypic spectrum and genetics of PAX2-related disorder in the Chinese cohort

Cited by 8 publications

References 24 publications

PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

Genetic diagnosis and renal biopsy findings in the setting of a renal genetics clinic

Impaired neural circuitry of hippocampus in Pax2 nervous system‐specific knockout mice leads to restricted repetitive behaviors

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