TABLE 1. Mutations in NUP93, NUP205 or XPO5 in 10 individuals from 8 families with steroid resistant nephrotic syndrome.
| Family -Indivi- dual |
Nucleotide change |
Amino acid change |
Exon (zygosity, Segregation) |
PPH2 score |
SIFT | Amino acid conservation to species |
Allelic loss of functiona (NPC localization/ depletion-addback/ SMAD interaction/ SMAD dependent transcription) |
EVS allele frequencies |
Gender | Ethnic origin |
Parental consan- guinity |
Age of onset (ESRD) |
Extrarenal manifestations |
Biopsy (at age) |
Therapy and response |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NUP93 | |||||||||||||||
| A2403 -21 |
c.1162C>T | p.Arg388Trp | 11 (het, p) | 0.940 | del | C. elegans | (+/-/+/-) | TT=0/TC=10/CC=6488 | F | Serbian | N | 6 yrs (6 yrs) |
HU | FSGS, tubulo-interstitial infiltrations, tubular dilation (6 yrs) | RTX (12 yrs) US: hyperechogenic kidneys |
| c.1772G>T | p.Gly591Val | 16 (het, m) | 1 | del | S. cerevisiae | (+/+/-/-) | TT=0/TG=2/GG=6496 | ||||||||
| A3256 -21 |
c.1326delG | p.Lys442Asn fs*14 | 12 (het, m) | NA | NA | NA | (-/-/-/-) | - | F | German | N | ∼3yrs (3 yrs) |
HU | FSGS, tubular atrophy, interstitial infiltrations (3yrs) | SRNS, CsA-PR, RTX (6 yrs)39 |
| c.1772G>T | p.Gly591Val | 16 (het, p) | 1 | del | S. cerevisiae | (+/+/-/-) | TT=0/TG=2/GG=6496 | ||||||||
| A1394 -21 |
c.1537+1G>A | del ex13 | 13 (het, m) | NA | NA | NA | (-/-/+/-) | AA=0/AG=1/GG=6496 | F | German | N | 3 yrs (4 yrs) |
HU, Marcus-Gunn-syndrome | FSGS, global sclerosis with immature glomeruli (3 yrs) | SRNS, RTX (4 yrs) |
| c.1772G>T | p.Gly591Val | 16 (het, p) | 1 | del | S. cerevisiae | (+/+/-/-) | TT=0/TG=2/GG=6496 | ||||||||
| A1626 -21 |
c.1772G>T | p.Gly591Val | 16 (hom, m, p) | 1 | del | S. cerevisiae | (+/+/-/-) | TT=0/TG=2/GG=6496 | M | Turkish | Y | 3 yrs (11 yrs) |
NP | FSGS (3 yrs) | SRNS, ACE-I |
| -22 | F | 6 yrs | NP | ACE-I | |||||||||||
| A1671 -21 |
c.1886A>G |
|
17 (hom, m) | 0.997 | del | S. cerevisiae | (+/+/-/-) | - | M | Turkish | Y | 1 yr (1 yr) |
HU | DMS/FSGS (15 mo) | SRNS, RTX (3 yrs) |
| A2241 -22 |
c.1886A>G |
|
17 (hom) | 0.997 | del | S. cerevisiae | (+/+/-/-) | - | M | Turkish | Y | 1 yr | HU | ND | SRNS |
| NUP205 | |||||||||||||||
| A1733 -21 |
c.5984T>C | p.Phe1995Ser | 43 (hom, m, p) | 0.888 | del | D. melanogaster | abrogation of NUP93 interaction | - | F | Turkish | N | 3 yrs (7 yrs) |
NP | FSGS (3.5 yrs) | RTX (7 yrs) SRNS |
| -22 | M | 2 yrs | BAV, AI, ARE | FSGS (3 yrs) | SPR | ||||||||||
| XPO5 | |||||||||||||||
| F1092 -21 |
c.1654G>A | p.Val552Ile | 15 (hom, m, p) | 0.45 | del | C. intestinalis | n/a | - | M | Turkish | Y | 2 yrs | Speech development delay | MCNS (2 yrs) No effacement | Primary SRNS with response to CsA |
ACE; angiotensin converting enzyme inhibitor; AI, Aortic insufficiency; ARE, Aortic root enlargement; BAV, bicuspid aortic valve; CsA, cyclosporin A; ESRD, end-stage renal disease; del, deleterious; F, female; FSGS, focal segmental glomerulosclerosis; het, heterozygous; HD, hemodialysis; hom, homozygous; HU, hematuria; m, maternal; M, male; MCNS, Minimal change Nephrotic syndrome; ND, not done; NP, not present; NPC, nuclear pore complex; p, paternal; PPH2 score humvar PolyPhen2 prediction score; PR, partial response; RTX, renal transplantation; SIFT, Sorting tolerant from intolerant; SPR, steroid partial response; SRNS, steroid resistant nephrotic syndrome; Y, yes; yrs, years; A Western European founder mutation is single underlined, and a Turkish founder mutation is double underlined.
“-” indicates a defect of the allele in one of the 4 assays of NUP93 function: localization to the NPC (Fig. 3a,d), assembly of a minimal nuclear membrane (depletion-addback assay, Fig.3b-c), interaction with SMAD4 / importin7 (Fig. 4), SMAD4 nuclear translocation, or SMAD dependent transcription (Fig. 5).