CRB2 – Steroid‑Resistant Nephrotic Syndrome

CRB2 encodes a polarity protein essential for proper podocyte function and the maintenance of the glomerular filtration barrier. Multiple independent studies have implicated biallelic mutations in CRB2 as a cause of steroid‑resistant nephrotic syndrome (SRNS), a condition characterized by resistance to conventional steroid therapy and a high risk of progression to end‑stage renal disease (PMID:26925547). Clinical reports from diverse cohorts, including Ashkenazi Jewish families and pediatric patients, consistently demonstrate compound heterozygous or homozygous pathogenic variants associated with the SRNS phenotype.

The overall clinical validity of the CRB2‑SRNS association is rated as Strong. At least 23 unrelated probands have been reported with CRB2 mutations, and segregation analysis in multiple families confirms the recessive inheritance pattern (PMID:26925547; PMID:27942854). These data, combined with recurrent findings of key variants, such as c.2400C>G (p.Asn800Lys), provide compelling genetic evidence that supports the association.

The genetic evidence underscores an autosomal recessive inheritance mode. A variety of variant types (including missense, frameshift, and nonsense mutations) have been observed, with the recurrent variant c.2400C>G (p.Asn800Lys) noted in multiple publications. Segregation studies further support the association, with an estimated 19 additional affected relatives across families exhibiting the pathogenic CRB2 genotype (PMID:27004616).

Functional assessment studies have reinforced the pathogenic role of CRB2 disruption in SRNS. In vitro assays and animal models, including zebrafish studies, have demonstrated that CRB2 mutations impair podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking, thereby mimicking the human SRNS pathology (PMID:25557779). These experiments provide moderate functional evidence that the loss of CRB2 function is mechanistically linked to the disease phenotype.

While CRB2 mutations have been reported in association with other phenotypes such as ciliopathies and retinal dystrophies, the bulk of evidence for SRNS remains robust and internally consistent. There are no substantial studies that dispute the role of CRB2 in SRNS, and the genetic and functional data converge on a common pathogenic mechanism.

In conclusion, the integration of genetic findings and functional assays strongly supports a pathogenic role for CRB2 in steroid‑resistant nephrotic syndrome. This association is critical for diagnostic decision‑making; patients suspected of SRNS should be evaluated for CRB2 mutations. Key take‑home sentence: CRB2 is pivotal for maintaining glomerular filtration barrier integrity, and its disruption mandates the inclusion of CRB2 analysis in SRNS diagnostic workflows.

References

• Clinical Genetics • 2016 • Expanding the phenotype of CRB2 mutations – A new ciliopathy syndrom PMID:26925547
• Pediatric Nephrology • 2017 • Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid‑resistant nephrotic syndrome PMID:27942854
• American Journal of Human Genetics • 2015 • Defects of CRB2 cause steroid‑resistant nephrotic syndrome PMID:25557779
• European Journal of Human Genetics • 2016 • Expansion of phenotype and genotypic data in CRB2‑related syndrome PMID:27004616

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