Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients.
BACKGROUND
Congenital nephrotic syndrome (NPHS1) is a rare disease inherited as an autosomally recessive trait. The NPHS1 gene mutated in NPHS1 children has recently been identified. The gene codes for nephrin, a cell-surface protein of podocytes. Two mutations, named Fin-major and Fin-minor, have been found in over 90% of the Finnish patients. In this study, we correlated the NPHS1 gene mutations to the clinical features and renal findings in 46 Finnish NPHS1 children.


METHODS
Clinical data were collected from patient files, and kidney histology and electron microscopy samples were re-evaluated. The expression of nephrin was studied using immunohistochemistry, Western blotting, and in situ hybridization.


RESULTS
Nephrotic syndrome was detected in most patients within days after birth regardless of the genotype detected. No difference could be found in neonatal, renal, cardiac, or neurological features in patients with different mutations. Nephrin was not expressed in kidneys with Fin-major or Fin-minor mutations, while another slit diaphragm-associated protein, ZO-1, stained normally. In electron microscopy, podocyte fusion and podocyte filtration slits of various sizes were detected. The slit diaphragms, however, were missing. In contrast to this, a nephrotic infant with Fin-major/R743C genotype expressed nephrin in kidney had normal slit diaphragms and responded to therapy with an angiotensin-converting enzyme inhibitor and indomethacin.


CONCLUSIONS
The most common NPHS1 gene mutations, Fin-major and Fin-minor, both lead to an absence of nephrin and podocyte slit diaphragms, as well as a clinically severe form of NPHS1, the Finnish type of congenital nephrotic syndrome.
Patrakka
J
J
Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
Kestilä
M
M
Wartiovaara
J
J
Ruotsalainen
V
V
Tissari
P
P
Lenkkeri
U
U
Männikkö
M
M
Visapää
I
I
Holmberg
C
C
Rapola
J
J
Tryggvason
K
K
Jalanko
H
H
D015153:Blotting, Western; D005387:Finland; D015870:Gene Expression; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D007019:Hypoproteinemia / Q000151:congenital / Q000235:genetics; D017403:In Situ Hybridization; D007231:Infant, Newborn; D007668:Kidney / Q000737:chemistry / Q000648:ultrastructure; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D008854:Microscopy, Electron; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000151:congenital / Q000235:genetics*; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D011507:Proteinuria / Q000151:congenital / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C113267:nephrin