
==== Front
Mol Genet Genomic Med
Mol Genet Genomic Med
10.1002/(ISSN)2324-9269
MGG3
Molecular Genetics & Genomic Medicine
2324-9269
John Wiley and Sons Inc. Hoboken

10.1002/mgg3.70006
MGG370006
MGG3-2024-02-0234.R3
Clinical Report
Clinical Report
Frameshift Mutation in PAX2 Related to Focal Segmental Glomerular Sclerosis: A Case Report and Literature Review
Hu Xueling https://orcid.org/0000-0003-0048-0967
1
Lin Wei 2
Luo Zengyuan 1
Zhong Yong 1
Xiao Xiangcheng 1
Tang Rong 1 tangrbsoon@126.com

1 Department of Nephrology, Xiangya Hospital Central South University Changsha China
2 Department of Pathology, Xiangya Hospital Central South University Changsha China
* Correspondence:
Rong Tang (tangrbsoon@126.com)

05 9 2024
9 2024
12 9 10.1002/mgg3.v12.9 e7000614 8 2024
01 3 2024
20 8 2024
© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

ABSTRACT

Background

Paired box gene 2 (PAX2) heterozygous mutations can cause renal coloboma syndrome, but its role in patients with focal segmental glomerular sclerosis (FSGS) has been rarely reported.

Methods

Based on the clinical manifestations and renal pathological characteristics of the patient, as well as familial whole exome sequencing, the diagnosis of FSGS related to PAX2 mutation was confirmed. Treatment such as lowering urinary protein and blood pressure was given, and the patient was followed up and observed.

Results

There is a familial heterozygous case presented with chronic kidney disease secondary to FSGS, which was related to PAX2 frameshift mutation due to the deletion of G at the position 76 (c.76delG). To our knowledge, this is the first report of PAX2 c.76delG variant related to adult‐onset FSGS.

Conclusion

Here, we further expand the phenotypic spectrum of FSGS. Genetic screening especially PAX2 mutation is recommended in patients with adult‐onset FSGS of unknown etiology.

We reported a familial heterozygous case presented with CKD secondary to FSGS, which was related to PAX2 frameshift mutation due to the deletion of G at the position 76 (c.76delG). The c.76delG frameshift mutation has been rarely associated with renal coloboma syndrome and reported in the area of neurological disorders. This is the first report of PAX2 c.76delG variant related to adult‐onset FSGS.

chronic kidney disease
focal segmental glomerular sclerosis
frameshift mutation
PAX2
source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:05.09.2024
Funding: This work was supported by grants from the Natural Science Foundation of Hunan Province (No. 2022JJ30070).
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pmcAbbreviations

ARB angiotensin receptor blocker

c.76delG the deletion of G at the position 76

CAKUT congenital anomalies of the kidney and urinary tract

CKD chronic kidney disease

eGFR estimated glomerular filtration rate

ESRD end‐stage renal disease

FSGS focal segmental glomerular sclerosis

GBM glomerular basement membrane

HD homeodomain

OP octapeptide

PAX2 paired box gene 2

PD paired domain

RCS renal coloboma syndrome

TD transactivation domain

TFs transcriptional factors

WES whole exome sequencing

1 Background

Focal segmental glomerular sclerosis (FSGS) is a pattern of renal pathological lesions caused by various etiologies mediating podocyte damage (Wiggins 2007; D'agati et al. 2004). Characterized by proteinuria with or without nephrotic range, FSGS is a common glomerular cause of end‐stage renal disease (ESRD). FSGS can be divided into primary (idiopathic), genetic, and secondary forms, with genetic factors increasingly recognized in its development. Several genes, such as INF2, ACTN4, and TRPC6, have been reported to be related to monogenic adult‐onset inherited FSGS (Brown et al. 2010; Chen and Liapis 2015). In recent years, the potential role of Paired box gene 2 (PAX2) [OMIM no. 167409] mutations in FSGS has garnered growing attention. PAX2 encodes a transcription factor that plays a crucial role in the development of the urogenital tract, eyes, nervous system, and ears (Lv et al. 2021; Harshman and Brophy 2012). Heterozygous PAX2 mutations can lead to congenital anomalies of the kidney and urinary tract (CAKUT) as part of renal coloboma syndrome (RCS), also called papillorenal syndrome, characterized by renal hypodysplasia and optic nerve dysplasia. Mutations in this gene can also cause isolated CAKUT without ocular or auditory anomalies. Although the relevance of heterozygous PAX2 mutations in chronic kidney disease (CKD) has been described, there is limited genetic information available regarding the potential role of PAX2 variants in adult‐onset FSGS (Vivante et al. 2019; Xiong et al. 2022). Recently, seven heterozygous mutations in PAX2 were identified in a familial cohort with adult‐onset FSGS, suggesting that PAX2 missense mutations might expand the phenotypic spectrum to include hereditary FSGS (Harshman and Brophy 2012). In this study, we report a PAX2 c.76delG variant detected by whole exome sequencing (WES) in a familial heterozygous case with adult‐onset FSGS in the absence of other congenital abnormalities.

2 Materials and Methods

2.1 Patient Selection and Clinical Assessment

A 36‐year‐old man, diagnosed with fatty liver in his medical records, presented to the outpatient Department of Nephrology at Xiangya Hospital due to worsening generalized fatigue and foamy urine for more than 1 year. His mother, uncle, and one of his brothers had ESRD with unknown etiology and were undergoing regular hemodialysis. There was no family medical history of diabetes mellitus. No ocular or auditory manifestations were recorded.

2.2 Physical Examination and Laboratory Testing

The patient's blood pressure was recorded at 145/90 mmHg, and his body mass index (BMI) was 30.28 kg/m2. Neither facial nor lower limb edema, nor percussion pain in the renal region, was found on examination. Laboratory tests before treatment revealed proteinuria 4+, total urine protein/creatinine 3.17 g/g, serum creatinine 149.8 μmol/L, estimated glomerular filtration rate (eGFR) 50.9 mL/min × 1.73 m2, triglyceride 9.13 mmol/L, serum albumin 44.9 g/L, and hemoglobin 152.0 g/L. An abdominal ultrasonography showed normal kidney size but enhanced renal parenchymal echo. Fundus photography displayed hypertensive retinopathy with vitreous opacity in both eyes.

2.3 Genetic Analysis

Based on the patient's family history, WES was recommended for the patient and his immediate family members. Blood samples were collected from six individuals, and high‐quality genomic DNA was extracted. WES was performed to enrich and sequence the exonic regions using the Illumina NovaSeq platform. The data were processed by aligning reads to a reference genome using BWA, detecting variants with GATK, and annotating them with ClinVar. Variants were filtered and interpreted based on their clinical relevance. The results revealed a heterozygous PAX2 mutation, c.76delG (p.Val26Cysfs*3), in the proband, his mother, brother, and two daughters, while his son was fortunately negative for the corresponding pathogenic variation (Figure 1). His daughters were asymptomatic, and other examinations showed no abnormalities. The reference sequence used for the PAX2 gene was GenBank accession number NG_008680.2. Sanger sequencing was subsequently conducted to validate the presence of the PAX2 c.76delG mutation, ensuring the accuracy of the WES results. (Figure 2).

FIGURE 1 Pedigree of the subject family in our study. The proband is indicated by an arrow. Black indicates the patients carrying the c.76delG variant.

FIGURE 2 Conformation of the c.76delG variant for the proband and his daughters by Sanger sequencing.

2.4 Renal Biopsy and Pathological Examination

To further clarify the diagnosis, a renal biopsy was performed. Four kidney tissues samples from the proband, each measuring 0.6–1.0 cm, were obtained for light microscopy examination (Figure S1A–D). There were 14 glomeruli in total, with 5 showing global sclerosis (35.7%) and 2 showing segmental sclerosis (14.3%). Glomerular lesions were mild, without crescent formation, but displayed thickening of the basement membrane of Bowman's capsule with a particularly narrow lumen and peribulbar fibrosis. Segmental mild mesangial proliferative changes, moderate to severe aggravation of individual glomerular segments, and a tendency toward segmental sclerosis were observed. The glomerular basement membrane (GBM) had no delamination or double track but showed segmental thickening. There were multifocal tubular atrophy (20%), shedding of brush borders, granule and vacuolar deformation of epithelial cells, and visible protein casts. Additionally, multifocal fibrotic hyperplasia and scatted inflammatory cell infiltration (20%) were presented. Immunofluorescence staining displayed the moderate deposition of IgM in the mesangial area with an intensity of 2+, while IgA, IgG, C3, C4, C1q, kappa light chain, and lambda light chain were negative. Electron microscopy of one glomerulus showed segmental glomerulosclerosis, with mesangial lesions including segmental mild hyperplasia and sclerosis, and a small amount of electron‐dense deposits in the stroma. Podocyte lesions were presented with extensive foot processes effacement. The GBM showed negative electron density. Slightly degeneration of granules and vacuoles in tubular epithelial cells was seen, but no obvious atrophy was found in renal tubules. Interstitial edema with scattered inflammatory cell infiltration was also observed (Figure S1E). Therefore, the complete renal pathological diagnosis was: (1) FSGS, with a high likelihood of association with PAX2 mutation; and (2) glomerular lesions presented as segmental proliferative and sclerotic change, and mesangial lesions with a very small amount of electron density.

2.5 Treatment and Follow‐Up

Angiotensin receptor blocker (ARB) irbesartan was prescribed for lowering blood pressure and proteinuria. Tripterygium glycosides and hydroxychloroquine were used to reduce the proteinuria and inflammation. Other treatment measures included modulation of dyslipidemia and supportive therapy. After 1 month, the patient's urine protein decreased to 2+, and the total 24‐h urine protein was 1.54 g. Immunosuppressive drugs were then stopped. After 9 months of treatment, the follow‐up results showed that proteinuria 2+, total urine protein/creatinine 1.7 g/g, serum creatinine 173.1 μmol/L, eGFR 42.8 mL/min × 1.73 m2, TC 7.44 mmol/L, and hemoglobin 144.0 g/L. The laboratory data before and after treatment are listed in Table 1. The overall condition is stable without significant progression, and hydroxychloroquine was used again.

TABLE 1 Laboratory values at the first admission and the time after treatment.

	0 month	1 month	9 months	11 months	
Hemoglobin (g/L)	156	152.0	144.0	—	
Serum albumin (g/L)	44.9	40.5	45.5	—	
Triglyceride (mmol/L)	9.13	6.2	7.44	5	
Total cholesterol (mmol/L)	5.15	5.86	4.73	—	
Proteinuria qualitative analysis	4+	2+	2+	2+	
Urinary protein (g/24 h)	—	1.54	—	—	
Total urine protein/creatinine (g/g)	3.17	1.38	1.7	—	
Serum uric acid (μmol/L)	444.6	490.7	473.5	—	
Serum creatinine (μmol/L)	149.8	157.5	173.1	153	
eGFR (mL/min per 1.73 m2)	50.9	48.0	42.5	49.3	
Abbreviation: eGFR, estimated glomerular filtration rate.

3 Discussion

Previous study has proposed that abnormal expression of PAX2 may promote glomerular hypoplasia with a reduced number of glomeruli even leading to CKD (Zhang et al. 2018). PAX2 is essential for proper kidney development, particularly in the communication between the ureteric bud and metanephric mesenchyme, which forms podocytes (Capone et al. 2017). At the molecular level, PAX2 functions as a transcription factor regulating genes indispensable for kidney cell differentiation and proliferation. During early kidney development, PAX2 expression is required to maintain the progenitor cell population in the nephrogenic zone, ensuring the proper formation of nephrons (Naiman et al. 2017). Abnormal PAX2 expression disrupts kidney development, leading to various malformations. Overexpression of PAX2 can inhibit nephron progenitor cell differentiation, resulting in multicystic dysplastic kidneys, which are filled with cysts and lack normal structures. Conversely, insufficient PAX2 expression can lead to renal hypodysplasia, characterized by underdeveloped kidneys with fewer nephrons (Zhang et al. 2018).

PAX2 is also vital for the development of the ureteric bud, which forms the collecting duct system. Dysregulation of PAX2 can impair this process, leading to CAKUT, such as vesicoureteral reflux (Kohl et al. 2021; Kagan, Pleniceanu, and Vivante 2022). Furthermore, PAX2 mutations are associated with RCS, which includes renal anomalies and optic nerve abnormalities. PAX2 mutations can disrupt the balance between cell proliferation and apoptosis in kidney tissues, contributing to abnormal kidney development and function (Sanna‐Cherchi et al. 2018).

Research on several FSGS patients revealed that PAX2 mutations may contribute to the familial form of FSGS (Table 2) (Vivante et al. 2019; Bower, Schimmenti, and Eccles 1993). These mutations can lead to podocyte dysfunction, a critical component of the glomerular filtration barrier, ultimately resulting in proteinuria and progressive kidney damage. We identified a PAX2 frameshift variant c.76delG (p.Val26Cysfs*3) in a family presenting with CKD without other congenital abnormalities, which followed an autosomal dominant inheritance pattern. Few reports have shown that this mutation is related to RCS and might hinder the development of the nervous system (Schimmenti et al. 1999). This study suggests that the PAX2 c.76delG frameshift mutation might be associated with the development of FSGS.

TABLE 2 Published case reports of clinical features of FSGS families with PAX2 mutation.

Family ID	DNA change	Amino acid change	Age of onset (year)	Persons affected (n)	Patients with ESRD (n)	ESRD age (year)	Patients with biopsy (n)	
FG‐BF	c.491C>A	p.Thr164Asn	8	2	1	Unknown	1	
FG‐DG	c.239C>T	p.Pro80Leu	7–11	2	Unknown	Unknown	Unknown	
FG‐EQ	c.565G>A	p.Gly189Arg	17–68	6	2	40–58	2	
FG‐GE	c.398C>T	p.Ser133Phe	Unknown	2	1	Unknown	1	
FG‐IX	c.167G>A	p.Arg56Gln	36	4	Unknown	Unknown	Unknown	
FG‐JO	c.448A>G	p.Thr150Ala	31–32	5	4	30–36	3	
FG‐KV	c.310C>T	p.Arg104×	15–24	3	1	42	3	
AN10	c.69_70insG	p.Val26Glyfs*28	2	1	1	4	1	
A4041	c.254G>T	p.Gly85Val	10–35	4	1	39	2	
A5089	c.862‐1G>A	Splice mutation	20	2	1	27	1	
A5281	c.275G>T	p.Thr92Met	18	3	2	50–70	1	
Note: Nucleotide and amino acid sequence changes are reported using the National Center for Biotechnology Information RefSeq accession numbers. PAX2: NG_008680.2.

The pathological and clinical characteristics of FSGS include segmental glomerular sclerosis, proteinuria, decreased glomerular filtration rate, and progressive decline in renal function (De Vriese et al. 2018; Rosenberg and Kopp 2017). Renal insufficiency often progresses to ESRD, requiring dialysis therapy or kidney transplantation (Sprangers, Meijers, and Appel 2016; Shabaka, Tato Ribera, and Fernández‐Juárez 2020). Notably, we observed three generations of a family with the same PAX2 mutation but different degrees of kidney manifestations. The proband was diagnosed with FSGS at the age of 36, exhibiting non‐nephrotic proteinuria, hypertension, and a decline in renal function, but no CAKUT phenotype. His affected family members carrying the same mutation progressed to ESRD. However, his two daughters had no symptoms. Due to the lack of specific treatment, genetic analysis should be recommended in such familial cases to avoid unnecessary immunosuppressants with significant side effects, and early treatment to protect the kidney can be initiated. Although the renal function of our patient is currently stable, he is being closely followed up and his treatment adjusted accordingly.

This case highlights the potential benefits of clarifying the diagnosis of such a heterogeneous disorder through genetic analysis to avoid unnecessary immunosuppressive agents. The molecular mechanisms of the c.76delG mutation in PAX2 in the development of glomerular lesions such as FSGS remain unclear. There are several possible speculations about the mechanisms of PAX2 mutations in FSGS.

First, PAX2 has 12 exons, and the encoded nuclear transcriptional factors (TFs) contain a DNA binding domain (paired domain, PD) at the N‐terminal, a conserved octapeptide (OP) motif, a partial or full homeodomain (HD), and a transactivation domain (TD) at the C‐terminal (Narahara et al. 1997). The deletion of a guanine nucleotide in a string of seven guanines in exon 2 leads to a premature stop codon three amino acids 3′ of the frameshift, which may alter the DNA binding function of the PD (Schimmenti et al. 1999).

Second, PAX2 plays a critical role in the proper interaction between ureteric bud and metanephric mesenchyme, which epithelializes to form podocytes during kidney development. Thus, a PAX2 mutation may affect the differentiation and maturation of podocytes (Naiman et al. 2017).

Third, the dysregulation of PAX2 expression may repress the expression of downstream targets, such as WT1, subsequently disrupting the development and/or function of podocytes (Mitrotti et al. 2024; Longaretti et al. 2021).

Most RCS‐related PAX2 mutations tend to generate truncated proteins leading to renal malformation and multi‐system involvement, while missense mutations in PAX2 are observed more frequently in FSGS cohorts (Muntean et al. 2023; Yang et al. 2021). However, the proband in our study with the c.76delG frameshift variant was confirmed to have FSGS lesions in the absence of other syndromic features, and his clinical manifestation is milder than that of his mother and brother. Current literature supports the possibility of clinical variability and phenotypic heterogeneity associated with the same PAX2 mutation. This may be illustrated by incomplete penetrance resulting from haploinsufficiency (Barua et al. 2014). Similarly, Chinese researchers have discovered a de novo PAX2 frameshift mutation (c.76_77insG, p.V26G fs28) in 15‐year‐old twin brothers, leading to the early onset of FSGS during childhood (Hu et al. 2021). This contrasts with our study where the PAX2 c.76delG mutation was associated with adult‐onset FSGS, highlighting the phenotypic variability and different ages of onset associated with PAX2 mutations. Regrettably, his mother and brother had no opportunity to receive a renal biopsy.

4 Conclusion

PAX2 mutation‐related disorders display distinct clinical variation and phenotypic heterogeneity. Here, we further expand the phenotypic spectrum of FSGS associated with PAX2 c.76delG variants, which have been previously identified in patients with CAKUT as part of RCS (Rasmussen et al. 2021). Our case emphasizes that genetic screening, especially for PAX2 mutation, is recommended in patients with adult‐onset FSGS of unknown etiology, with or without family involvement, even if urogenital abnormalities are absent. Long‐term follow‐up and regular examinations of urinalysis and renal function are necessary for the patients in our study.

Author Contributions

Xueling Hu: writing – original draft, writing – review and editing, patient enrollment, and follow‐up. Zengyuan Luo: writing – original draft, patient follow‐up. Wei Lin: pathological specimens analysis and diagnosis. Rong Tang: data curation, writing – review, and editing. Yong Zhong: writing – review and editing. Xiangcheng Xiao: conceptualization, patient enrollment, and follow‐up. All authors read and approved the submitted version.

Ethics Statement

This study was approved by the ethics committee of Xiangya Hospital, Central South University, ensuring compliance with all relevant ethical guidelines.

Consent

Informed consent was obtained from the patients for publication of this case report.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Supporting information

Figure S1: Renal histologic lesions of the proband. (A) Segmental glomerulosclerosis and endothelial cell proliferation in the glomerulus (HE; scale bar: 50 μm). (B) Thickening of basement membrane of Bowman's capsule with peribulbar fibrosis (Masson; scale bar: 50 μm). (C) Segmental thickening of glomerular basement membrane in the glomerulus (PASM; scale bar: 50 μm). (D) Granular or vacuolar degeneration of renal tubular epithelial cells and multifocal atrophy of tubules (PAS; scale bar: 50 μm). (E) Electron microscopy showed mild to moderate hyperplasia of mesangium, segmental sclerosis of glomerulus, and focal renal interstitial fibrosis, with extensive podocytes foot processes effacement (magnification: ×1200).

Acknowledgments

The authors thank all of the staff of the Department of Nephrology and the nursing staff for their dedicated assistance in patient follow‐up data collection.

Data Availability Statement

All data generated or analyzed during this study are included in this published article.
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