Table 1.
Dominant NRIP1 mutation detected in individuals with CAKUTa
| Family – Individuala,b,c | Presenting Symptoms or Diagnostic Test (at Age in yr) | Kidney Phenotype | Treatment | Serum Creatinine, mg/dl (at Age in yr) |
|---|---|---|---|---|
| H | ||||
| II:8 | Renal US (69) | R small pelvic kidney with hydronephrosis | Conservative | 0.93 (69) |
| III:3 | Abdominal mass (newborn) | L MCDK; R VUR, dilated ureter, and dysplasia | L nephrectomy | 1.5 (35) |
| R nephrostomy | ||||
| III:4 | Abdominal pain (7) | L dysplastic kidney and VUR | L nephrectomy | 0.75 (27) |
| III:5 | Renal US and VCUG (3) | Bilateral grade 2 VUR | Conservative | 0.64 (28) |
| IV:7 | Renal US (2) | Small right kidney | Conservative | 0.23 (5) |
| IV:8 | Hydronephrosis on renal US (prenatal) | L VUR grade 5 and dysplasia; R VUR grade 2 | Conservative | 0.45 (8) |
| IV:9 | Renal US (prenatal) | L ectopic dysplastic kidney | Conservative | 0.23 (3) |
Co-IP, coimmunoprecipitation; k.d., knock-down; US, ultrasound; R, right; L, left; MCDK, multicystic dysplastic kidney; VCUG, voiding cystourethrogram.
All individuals were found to harbor a c.279delG mutation in NRIP1. The cDNA mutation is numbered according to human cDNA reference sequence NM_003489.3, isoform (NRIP1), where +1 corresponds to the A of ATG start translation.
The c.279delG NRIP1 mutation corresponds to the following alteration in the coding sequence: p.Trp93fs*. This mutation was absent from 200 control individuals with renal ciliopathies, 429 individuals with steroid-resistant nephrotic syndrome, from approximately 13,000 healthy control alleles of the EVS (http://evs.gs.washington.edu/EVS), from 2577 control individuals of the “1000 genomes project” (http://www.1000genomes.org), and from approximately 100,000 control chromosomes of the ExAC server (http://exac.broadinstitute.org). In addition, NRIP1 had an ExAC: pLI (probability of being loss-of-function intolerant) score of 0.99. The closer the pLI is to 1, the more loss-of-function-intolerant the gene appears to be. Genes with pLI≥0.9 are considered as an extremely loss-of-function-intolerant set of genes.
Loss of function of the NRIP1 c.279delG allele was demonstrated in four assays: nuclear localization (Figures 2A and 2B), luciferase assay (Figure 2C), co-IP with RARα (Figure 3A), or Xenopus knockdown and rescue experiments (Figure 5, D–K).