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Abstract: PO1983

Collapsing FSGS in Siblings with Compound Heterozygous Variants in NUP93 Expand the Spectrum of Kidney Phenotype Associated with NUP93 Mutations

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Cason, Rachel Kate, Duke University Health System, Durham, North Carolina, United States
  • Williams, Anna E., Duke University Health System, Durham, North Carolina, United States
  • Chryst-Stangl, Megan, Duke University Health System, Durham, North Carolina, United States
  • Wu, Guanghong, Duke University Health System, Durham, North Carolina, United States
  • Brathwaite, Kaye E., Montefiore Health System, Bronx, New York, United States
  • Lane, Brandon M., Duke University Health System, Durham, North Carolina, United States
  • D'Agati, Vivette D., Columbia University Irving Medical Center, New York, New York, United States
  • Gbadegesin, Rasheed A., Duke University Health System, Durham, North Carolina, United States
Introduction

Focal segmental glomerulosclerosis (FSGS) is a major cause of end stage kidney disease, the collapsing form has the worst prognosis. Study of families with hereditary FSGS has provided insight into disease mechanisms. In this report, we describe a sibling pair with NUP93 mutations and collapsing FSGS. This is the first report of collapsing FSGS associated with NUP93 mutations.

Case Description

We identified a Caucasian sibling pair with early onset steroid resistant nephrotic syndrome. Kidney biopsy in both brothers performed at ages 5 and 2 years, respectively, showed collapsing FSGS. Lesions of segmental or global sclerosis with focal collapsing features involved 22/33 and 6/28 glomeruli, respectively. Clinical phenotypes are summarized in Table 1. We obtained DNA from the affected brothers and their unaffected parents and carried out whole genome sequencing on the two affected siblings. We applied our standard filtering algorithm1 and identified segregating rare compound heterozygous variants 1) C.1772G>T p.G591V, 2) c.2084T>C p.L695S in NUP93 in the two affected brothers. Both variants are rare with minor allele frequency <0.00015. Both variants are evolutionarily conserved and were predicted to be pathogenic by four in-silico tools. 3D modeling revealed that both variants created structural alterations throughout the protein including the amino and the carboxyl terminal residues. These structural alterations are predicted to alter the binding affinity for several NUP93 ligands, likely disrupting the function of the highly organized nuclear pore channel.

Discussion

To the best of our knowledge, this is the first report of collapsing FSGS in patients with NUP93 mutations. Functional studies to determine the mechanisms by which these variants cause podocytopathy may provide insight into the pathogenesis of the more common idiopathic and virus-mediated forms of collapsing FSGS as well as aid in early disease detection and intervention.

Table 1 - Clinical Phenotypes
SubjectAge at disease onset (yr)Proteinuria (g)Age at ESKD (yr)Kidney Transplant (Y/N)Recurrence (Y/N)
15257YN
223.6unknownYN