GLIS2 – Nephronophthisis

GLIS2 has emerged as a critical player in the pathogenesis of nephronophthisis, an autosomal recessive ciliopathy characterized by chronic tubulointerstitial nephritis, progressive renal failure, and a range of extrarenal manifestations (PMID:18607645). Several independent studies across diverse cohorts have investigated the genetic underpinnings of this disorder, consistently implicating GLIS2 in its etiology.

Genetic evidence is compelling. A case report detailed a consanguineous family in which a novel homozygous in-frame deletion, c.560_574delACCATGTCAACGATT (p.His188_Tyr192del) (PMID:34917135), segregated with nephronophthisis. This result is supported by multi‐patient exome sequencing studies that identified pathogenic mutations in GLIS2 among 32 families (PMID:26489029), underscoring a strong gene–disease association.

The variant spectrum for GLIS2 includes disruptions that affect key functional domains, particularly the zinc finger motifs essential for its role in transcriptional regulation. The reported in-frame deletion disrupts the alpha-helical structure within a zinc-finger domain, likely resulting in misfolding and loss of function consistent with the disease phenotype.

Functional studies further strengthen the association. Multiple assays have demonstrated that GLIS2 is essential for proper nuclear localization and transcriptional regulation. Experimental work shows that mutations in GLIS2 impair DNA binding and transactivation functions (PMID:21127075; PMID:26374130), and animal models of Glis2 deficiency recapitulate key features of nephronophthisis, including renal fibrosis and tubular atrophy.

Although some investigations have proposed potential roles for GLIS2 beyond classical ciliary function, the preponderance of evidence from segregation analyses, variant impact studies, and functional assays consistently supports a pathogenic mechanism rooted in altered transcriptional regulation.

In summary, the integration of robust genetic findings—including segregation in consanguineous families and identification of a disruptive in-frame deletion—with corroborative functional data confirms a strong association between GLIS2 and nephronophthisis. This evidence not only informs diagnostic decision‑making but also underscores the gene’s potential as a target for future therapeutic strategies.

References

• Pediatric Nephrology • 2009 • Nephronophthisis PMID:18607645
• Kidney International • 2016 • Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity PMID:26489029
• Frontiers in Genetics • 2021 • Case Report: A Novel In-Frame Deletion of GLIS2 Leading to Nephronophthisis and Early Onset Kidney Failure PMID:34917135
• The Journal of Biological Chemistry • 2011 • Identification of nuclear localization, DNA binding, and transactivating mechanisms of Kruppel-like zinc finger protein Gli-similar 2 (Glis2) PMID:21127075
• European Journal of Human Genetics • 2016 • The C175R mutation alters nuclear localization and transcriptional activity of the nephronophthisis NPHP7 gene product PMID:26374130

Evidence Based Scoring (AI generated)