Wilms’ tumour 1 gene mutations in south Indian children with steroid-resistant nephrotic syndrome

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Abstract

Background & objectives:

Clinically, nephrotic syndrome (NS) is a diverse group of symptoms; about 20 per cent of NS cases are resistant to steroid treatment, and within ten years they progress to end-stage renal disease. The present study was undertaken to identify the mutations of Wilms’ tumour 1 ( WT1) gene in steroid-resistant NS (SRNS) children.

Methods:

A total of 173 children with SRNS and 100 children in the control group were enrolled in the study. DNA extraction was done, screened for WT1 (exons 8 and 9) gene amplified by polymerase chain reaction and direct sequencing. Karyotype analyses were done for WT1 mutation cases.

Results:

WT1 mutations were found in three of 173 SRNS cases (2 girls, 1 boy). All of them had intron 9 (IVS 9 + 4 C>T, 2; IVS + 5 G>A, 1) mutation. Of these three cases, one had familial and another two had sporadic history. Renal histology analysis showed two cases with focal segmental glomerulosclerosis (FSGS) and they had external female genitalia but 46, XY karyotype. Both of them had streak gonads. Of the three cases, one expired.

Interpretation & conclusions:

The findings of the present study indicate that all females with SRNS-FSGS should be screened for WT1 gene mutation to diagnose whether they have FS for possible gonadectomy.

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Most cited references 29

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Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).

Martin Zenker, Rasheed Gbadegesin, Friedhelm Hildebrandt … (2007)

Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations. We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage. We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment. First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.

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Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation.

D Landrock, A Hammes, U Ziegler … (2001)

Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.

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Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE).

R E Portman, R E Hogg, F Ingelfinger … (2000)

The development of this review article evolved from a National Kidney Foundation consensus conference on recent advances in the importance of evaluating and treating proteinuria. From this conference, a series of recommendations for the evaluation of adults with proteinuria was published. Because specific pediatric aspects of the problem were outside the scope of the original National Kidney Foundation publication, an ad hoc committee of 6 pediatric nephrologists who were active participants in the National Kidney Foundation conference was established to provide primary care physicians with a concise, up-to-date reference on this subject. The recommendations that are given represent the consensus opinions of the authors. These are based on data from controlled studies in children when available, but many of the opinions are, by necessity, based on uncontrolled series in children or controlled trials performed in adults, because controlled trials in children have not been performed to evaluate many of the treatments described. These recommendations are intended to provide primary care physicians with a useful reference when they are faced with a young child or teenager who presents with proteinuria, whether this is mild and asymptomatic or more severe, leading to nephrotic syndrome.

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Author and article information

Journal

Journal ID (nlm-ta): Indian J Med Res

Journal ID (iso-abbrev): Indian J. Med. Res

Journal ID (publisher-id): IJMR

Title: The Indian Journal of Medical Research

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 0971-5916

Publication date (Print): August 2016

Volume: 144

Issue: 2

Pages: 276-280

Affiliations

[1 ] Department of Paediatric Nephrology, Institute of Child Health and Hospital for Children, Madras Medical College, Chennai, India

[2 ] Department of Medical Genetics, Tamil Nadu Dr. M.G.R. Medical University, Guindy, India

[3 ] Department of Animal Genetics and Breeding, Madras Veterinary College, Chennai, India

[4 ] Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai, India

Author notes

Reprint requests: Dr Prabha Senguttuvan, Department of Paediatric Nephrology, Dr. Mehta's Children's Hospital, Chetpet, Chennai 600 031, Tamil Nadu, India e-mail: prabha.sengu@ 123456gmail.com

Article

Publisher ID: IJMR-144-276

DOI: 10.4103/0971-5916.195044

PMC ID: 5206881

PubMed ID: 27934809

SO-VID: ef8c62ad-6620-4b2c-9e12-0212ebef1def

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Wilms’ tumour 1 gene mutations in south Indian children with steroid-resistant nephrotic syndrome

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Abstract

Background & objectives:

Methods:

Results:

Interpretation & conclusions:

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Journal of Medical Education Research

Most cited references 29

Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).

Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation.

Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE).

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