&lt;b&gt;&lt;i&gt;PAX2&lt;/i&gt;&lt;/b&gt; Mutation-Related Oligomeganephronia in a Young Adult Patient

Bito, Laszlo Z.; Kalmár, Tibor; Maróti, Zoltán; Turkevi-Nagy, Sándor; Bereczki, Csaba; Iványi, Béla

doi:10.1159/000510841

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…The etiology of OMN is often associated with genetic pathogenic variants, such as PAX2 , HNF1‐β , RET pathogenic variants, and chromosome 4 deletions. (Bitó et al, 2020; Gatto et al, 2018; Sagen et al, 2003; Sugimoto et al, 2016). Our patient's WES analysis revealed a novel heterozygous variation in the PBX1 gene with a pathogenic variant at c.262 delA, p.Thr88Glnfs*3 (Figure 1h).…”

Section: Discussionmentioning

confidence: 99%

A novel pathogenic variant c.262delA in PBX1 causing oligomeganephronia identified using whole‐exome sequencing and a literature review

Hu,

Yang,

Wang

et al. 2023

American J of Med Genetics Pt A

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Oligomeganephronia (OMN) is a rare congenital renal hypoplasia reported more often in children than in adults. The diagnosis of OMN relies on renal biopsy and exhibits a significant reduction in the number of glomeruli and pronounced glomerular hypertrophy. Here, we report the case of an 8‐year‐old boy with recurrent proteinuria and abnormal external ears. A renal biopsy revealed large and rare glomeruli. The histological findings confirmed the diagnosis of OMN. Whole‐exome sequencing of the patient revealed a new pathogenic variant in PBX1 (hg19, NM_002585, c.262delA, p.Thr88Glnfs*3). The PBX1 gene encodes a transcription factor whose pathogenic variants can result in congenital renal and urinary system anomalies, with or without hearing loss, abnormal ears, and developmental retardation (CAKUTED). This is the first report to detect PBX1 pathogenic variants in children with OMN, a novel phenotype of human PBX1 pathogenic variants. We performed functional prediction analyses of deletions in the corresponding structural domains. We summarized 27 cases of PBX1 single pathogenic variants reported between 2003 and 2023 in terms of truncating and missense pathogenic variants, which can deepen our understanding of the PBX1 structural domain and expand our knowledge of the PBX1 genotype and phenotype.

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Section: Discussionmentioning

confidence: 99%

A novel pathogenic variant c.262delA in PBX1 causing oligomeganephronia identified using whole‐exome sequencing and a literature review

Hu,

Yang,

Wang

et al. 2023

American J of Med Genetics Pt A

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“…A follow-up study in a pediatric cohort of steroid-resistant nephrotic syndrome and FSGS presented additional evidence of phenotypic expansion of extremely rare pathogenic PAX2 SNVs with the identification of heterozygous missense SNVs in 1.3% of cases [12]. Since the publication of these landmark papers, others, too, have reported on the incidence of PAX2 mutations in nonsyndromic FSGS (see Table 1) [35‒42].…”

Section: Pax2: a Kidney Development Gene Attributed To Cause Isolated...mentioning

confidence: 99%

Developmental Causes of Focal Segmental Glomerulosclerosis

Shane Klomp,

Levtchenko,

Westland

2024

Glomerular Dis

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Background: Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that includes idiopathic conditions as well as genetic and non-genetic forms. Among these various etiologies, different phenotypes within the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) have been associated with FSGS. Summary: Until recently, the main pathomechanism of how congenital kidney and urinary tract defects lead to FSGS was attributed to a reduced number of nephrons, resulting in biomechanical stress on the remaining glomeruli, detachment of podocytes, and subsequent inability to maintain normal glomerular architecture. The discovery of deleterious single-nucleotide variants in PAX2, a transcription factor crucial in normal kidney development and a known cause of papillorenal syndrome, in individuals with adult-onset FSGS without congenital kidney defects has shed new light on developmental defects that become evident during podocyte injury. Key Message: In this mini-review, we challenge the assumption that FSGS in CAKUT is caused by glomerular hyperfiltration alone and hypothesize a multifactorial pathogenesis that includes overlapping cellular mechanisms that are activated in both damaged podocytes as well as nephron progenitor cells.

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“…Two conditions were considered in a differential diagnosis. One was oligomeganephronia of adult-onset type [6,7], which is a very rare entity and sometimes may be caused by PAX2 mutations [6,8]. The other entity was obesity-related adaptive FSGS [1,9].…”

Section: Renal Biopsy Findings and Genetic Analysismentioning

confidence: 99%

Phenotype–Genotype Correlations in Three Different Cases of Adult-Onset Genetic Focal Segmental Glomerulosclerosis

Kalmár,

Turkevi-Nagy,

Bitó

et al. 2023

IJMS

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This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.

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<b><i>PAX2</i></b> Mutation-Related Oligomeganephronia in a Young Adult Patient

Cited by 5 publications

References 14 publications

A novel pathogenic variant c.262delA in PBX1 causing oligomeganephronia identified using whole‐exome sequencing and a literature review

A novel pathogenic variant c.262delA in PBX1 causing oligomeganephronia identified using whole‐exome sequencing and a literature review

Developmental Causes of Focal Segmental Glomerulosclerosis

Phenotype–Genotype Correlations in Three Different Cases of Adult-Onset Genetic Focal Segmental Glomerulosclerosis

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