Clinical and genetic variability of PAX2-related disorder in the Japanese population

Rossanti, Rini; Morisada, Naoya; Nozu, Kandai; Kamei, Koichi; Horinouchi, Tomoko; Yamamura, Takehira; Minamikawa, Shogo; Fujimura, Junya; Nagano, China; Sakakibara, Noburu; Ninchoji, Takeshi; Kono, Hiroshi; Ito, Shuichi; Tanaka, Ryojiro; Iijima, Kazumoto

doi:10.1038/s10038-020-0741-y

Cited by 18 publications

(32 citation statements)

References 27 publications

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“…A frameshift deletion of PAX2 in a family with optic nerve colobomas, renal hypoplasia and VUR (Sanyanusin et al, 1995) represents the first reported single gene defect causation of congenital anomalies of the kidney and urinary tract (CAKUT). Subsequently, larger patient cohort studies confirmed PAX2 mutations as an important cause of syndromic CAKUT and the establishment of RCS as a separate disease entity (Madariaga et al, 2013; Rossanti et al, 2020; Thomas et al, 2011; Weber et al, 2006). PAX2 is a member of the paired box (PAX) family of transcriptional regulatory genes with nine members described in humans.…”

Section: Discussionmentioning

confidence: 97%

Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia

Stevenson

Pagnamenta

Reichart

et al. 2020

American J of Med Genetics Pt A

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Hereditary hyperuricemia may occur as part of a syndromic disorder or as an isolated nonsyndromic disease, and over 20 causative genes have been identified. Here, we report the use of whole genome sequencing (WGS) to establish a diagnosis in a family in which individuals were affected with gout, hyperuricemia associated with reduced fractional excretion of uric acid, chronic kidney disease (CKD), and secondary hyperparathyroidism, that are consistent with familial juvenile hyperuricemic nephropathy (FJHN). However, single gene testing had not detected mutations in the uromodulin (UMOD) or renin (REN) genes, which cause approximately 30-90% of FJHN. WGS was therefore undertaken, and this identified a heterozygous c.226G>C (p.Gly76Arg) missense variant in the paired box gene 2 (PAX2) gene, which co-segregated with renal tubulopathy in the family. PAX2 mutations are associated with renal coloboma syndrome (RCS), which is characterized by abnormalities in renal structure and function, and anomalies of the optic nerve. Ophthalmological examination in two adult brothers affected with hyperuricemia, gout, and CKD revealed the presence of optic disc pits, consistent with optic nerve coloboma, thereby revising the diagnosis from FJHN to RCS. Thus, our results demonstrate the utility of WGS analysis in establishing the correct diagnosis in disorders with multiple etiologies.

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Section: Discussionmentioning

confidence: 97%

Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia

Stevenson

Pagnamenta

Reichart

et al. 2020

American J of Med Genetics Pt A

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“…A wide variety of clinical phenotypes have been reported in individuals with PAX2- related disorder [ 8 , 9 , 11 ]. Dysplasia of the optic nerve was the main ophthalmological finding of the disorder, which covered 63% of literature-based cases.…”

Section: Discussionmentioning

confidence: 99%

“…It is important for cell lineage specification in multicellular organisms [ 19 ]. A broad variety of non-renal and non-ophthalmological manifestations have been recorded in individuals with PAX2 -related disorders [ 3 , 11 , 20 ]. We should pay more attention to clinical assessment and tracking of multiple system development in the patient cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Haploinsufficiency of PAX2 has been reported among the patients with RCS, CAKUT or focal segmental glomerular sclerosis (FSGS) caused by the likely/presumed gene disruptive (LGD) variants or missense variants that may mimic haploinsufficiency. However, despite many reports of pathogenic variants in the PAX2 gene, there have been few reports revealing a consistent genotype–phenotype correlation [ 6 , 8 , 11 ].

Fig.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

et al. 2021

BMC Med Genomics

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Background Pathogenic variants of PAX2 cause autosomal-dominant PAX2-related disorder, which includes variable phenotypes ranging from renal coloboma syndrome (RCS), congenital anomalies of the kidney and urinary tract (CAKUT) to nephrosis. Phenotypic variability makes it difficult to define the phenotypic spectrum associated with genotype. Methods We collected the phenotypes in patients enrolled in the China national multicenter registry who were diagnosed with pathogenic variant in PAX2 and reviewed all published cases with PAX2-related disorders. We conducted a phenotype-based cluster analysis by variant types and molecular modeling of the structural impact of missense variants. Results Twenty different PAX2 pathogenic variants were identified in 32 individuals (27 families) with a diagnosis of RCS (9), CAKUT (11) and nephrosis (12) from the Chinese cohort. Individuals with abnormal kidney structure (RCS or CAKUT group) tended to have likely/presumed gene disruptive (LGD) variants (Fisher test, p < 0.05). A system review of 234 reported cases to date indicated a clear association of RCS to heterozygous loss-of-function PAX2 variants (LGD variants). Furthermore, we identified a subset of PAX2 missense variants in DNA-binding domain predicted to affect the protein structure or protein-DNA interaction associated with the phenotype of RCS. Conclusion Defining the phenotypic spectrum combined with genotype in PAX2-related disorder allows us to predict the pathogenic variants associated with renal and ophthalmological development. It highlighted the approach of structure-based analysis can be applied to diagnostic strategy aiding precise and timely diagnosis.

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“…The crucial role of the Pax2 genes in brain development and function have become apparent in recent reports on Pax2 -related diseases in a Japanese population describing that the patients with Pax2 mutations exhibit developmental abnormalities, including autism spectrum disorders (ASDs), language delay, or mental retardation. 7 , 8 Emerging evidence demonstrates that PAX2 proteins execute important functions during central nervous system development and in adult neurogenesis. 9–15 However, the molecular mechanisms required to establish and maintain these functional connections are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

The Role of PAX2 in Neurodevelopment and Disease

Lv¹,

Wang²,

Zhao³

et al. 2021

NDT

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In developmental biology, transcription factors are involved in regulating the process of neural development, controlling the differentiation of nerve cells, and affecting the normal functioning of neural circuits. Transcription factors regulate the expression of multiple genes at the same time and have become a key gene category that is recognized to be disrupted in neurodevelopmental disorders such as autism spectrum disorders. This paper briefly introduces the expression and role of PAX2 in neurodevelopment and discusses the neurodevelopmental disorders associated with Pax2 mutations and its possible mechanism. Firstly, mutations in the human Pax2 gene are associated with abnormalities in multiple systems which can result in neurodevelopmental disorders such as intellectual disability, epilepsy and autism spectrum disorders. Secondly, the structure of Pax2 gene and PAX2 protein, as well as the function of Pax2 gene in neural development, was discussed. Finally, a diagram of the PAX2 protein regulatory network was made and a possible molecular mechanism of Pax2 mutations leading to neurodevelopmental disorders from the perspectives of developmental process and protein function was proposed.

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Clinical and genetic variability of PAX2-related disorder in the Japanese population

Cited by 18 publications

References 27 publications

Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia

Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia

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

The Role of PAX2 in Neurodevelopment and Disease

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