Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome

Sako, Mayumi; Nakanishi, Koichi; Obana, Mina; Yata, Nahoko; Hoshii, Sakurako; Takahashi, Shori; Wada, Naohiro; Takahashi, Yoshio; Kaku, Yoshitsugu; Satomura, Kenichi; Ikeda, Masahiro; Honda, Masashi; Iijima, Kazumoto; Yoshikawa, Norishige

doi:10.1111/j.1523-1755.2005.00202.x

Cited by 84 publications

(71 citation statements)

References 27 publications

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“…Another striking feature in ILK-deficient podocyte is the aberrant distribution of ␣-actinin-4, an actin cross-linking protein that binds to actin filaments (37,38). Genetic mutations in ␣-actinin-4 gene have been shown to cause an autosomal dominant focal segmental glomerulosclerosis in patients (39).…”

Section: Discussionmentioning

confidence: 99%

Essential Role of Integrin-Linked Kinase in Podocyte Biology

Dai¹,

Stolz²,

Bastacky³

et al. 2006

Journal of the American Society of Nephrology

133

140

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Integrin-linked kinase (ILK) has been implicated in the pathogenesis of proteinuria and congenital nephrotic syndrome. However, the function of ILK in glomerular podocyte in a physiologic setting remains unknown. In this study, a mouse model was generated in which ILK gene was selectively disrupted in podocytes by using the Cre-LoxP system. Podocyte-specific ablation of ILK resulted in heavy albuminuria, glomerulosclerosis, and kidney failure, which led to animal death beginning at 10 wk of age. Podocyte detachment and apoptosis were not observed at 4 wk of age, when albuminuria became prominent, indicating that they are not the initial cause of proteinuria. Electron microscopy revealed an early foot process effacement, as well as morphologic abnormality, in ILK-deficient podocytes. ILK deficiency caused an aberrant distribution of nephrin and ␣-actinin-4 in podocytes, whereas the localization of podocin and synaptopodin remained relatively intact. Co-immunoprecipitation demonstrated that ILK physically interacted with nephrin to form a ternary complex, and ␣-actinin-4 participated in ILK/nephrin complex formation. Therefore, ILK plays an essential role in specifying nephrin and ␣-actinin-4 distribution and in maintaining the slit diaphragm integrity and podocyte architecture. These results also illustrate that the integrin and slit diaphragm signals in podocytes are intrinsically coupled through an ILK-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Essential Role of Integrin-Linked Kinase in Podocyte Biology

Dai¹,

Stolz²,

Bastacky³

et al. 2006

Journal of the American Society of Nephrology

133

140

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“…Recent whole-exome sequencing performed on a paediatric cohort of SRNS patients revealed the mean age of onset associated with NPHS2 mutations to be approximately 6 years [8]. That said, it is clearly important to consider NPHS2 mutation as a cause for SRNS in a child of any age and, conversely, to expect a low rate of NPHS2 mutations in certain ethnic groups, namely Chinese, Japanese and Korean [10,70]. Additionally, NPHS1 mutations have been identified in infants and children presenting with SRNS, with the rarer hypomorphic mutations being associated with a milder lateonset phenotype [8,71,72].…”

Section: Infantile and Childhood Nsmentioning

confidence: 99%

“…This is especially true for patients of Chinese, Japanese and Korean origin, as there appears to be an increased frequency of the ADCK4 mutation in these populations [10,70]. Additionally, given that the APOL1 genotype represents a vulnerable population who present with more advanced disease [108], defining a patient's APOL1 genotype has important clinical implications, and mutational screening of this gene should be included in the gene panel, especially for patients of African descent.…”

Section: Approach To Mutational Screeningmentioning

confidence: 99%

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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“…NPHS2, encoding for podocin, was identified as the causative gene in early-onset autosomal-recessive (AR) SRNS (11). Nevertheless, NPHS2 mutations have also been found in CNS (12)(13)(14)(15) and in a few cases of adult-onset FSGS (16 -18). Mutations of phospholipase C-(PLCE1) have been identified in 10 to 50% of patients with NS and diffuse mesangial sclerosis (DMS) and in 12% of familial AR FSGS (19 -22).Mutations in exons 8 and 9 of the Wilms tumor suppressor gene (WT1) were discovered in patients with syndromic SRNS (23,24) but can also cause isolated SRNS (25,26).…”

Section: Introductionmentioning

confidence: 99%

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

Santín

Bullich

Tazón-Vega

et al. 2011

Clinical Journal of the American Society of Nephrology

197

172

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SummaryBackground and objectives The increasing number of podocyte-expressed genes implicated in steroid-resistant nephrotic syndrome (SRNS), the phenotypic variability, and the uncharacterized relative frequency of mutations in these genes in pediatric and adult patients with SRNS complicate their routine genetic analysis. Our aim was to compile the clinical and genetic data of eight podocyte genes analyzed in 110 cases (125 patients) with SRNS (ranging from congenital to adult onset) to provide a genetic testing approach.Design, setting, participants, & measurements Mutation analysis was performed by sequencing the NPHS1, NPHS2, TRPC6, CD2AP, PLCE1, INF2, WT1 (exons 8 and 9), and ACTN4 (exons 1 to 10) genes. ResultsWe identified causing mutations in 34% (37/110) of SRNS patients, representing 67% (16/24) familial and 25% (21/86) sporadic cases. Mutations were detected in 100% of congenital-onset, 57% of infantileonset, 24 and 36% of early and late childhood-onset, 25% of adolescent-onset, and 14% of adult-onset patients. The most frequently mutated gene was NPHS1 in congenital onset and NPHS2 in the other groups. A partial remission was observed in 7 of 26 mutation carriers treated with immunosuppressive agents and/or angiotensin-converting enzyme inhibitors. Patients with NPHS1 mutations showed a faster progression to ESRD than patients with NPHS2 mutations. None of these mutation carriers relapsed after kidney transplantation. ConclusionsWe propose a genetic testing algorithm for SRNS based on the age at onset and the familial/ sporadic status. Mutation analysis of specific podocyte-genes has a clinical value in all age groups, especially in children.

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Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome

Abstract: These studies demonstrate that mutation of NPHS1 is not a major cause of CNS in Japanese patients, and that mutation of NPHS2 can be responsible for CNS in this population.

Cited by 84 publications

References 27 publications

Essential Role of Integrin-Linked Kinase in Podocyte Biology

Essential Role of Integrin-Linked Kinase in Podocyte Biology

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

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