NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum.
Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal-recessive form of nonsyndromic steroid-resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid-resistant nephrotic syndrome before the age of 6 years and rapidly progress to end-stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype-phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database (www.lovd.nl/NPHS2) software that will allow the inclusion of future reports.
Assistance Publique-Hôpitaux de Paris, Service de Néphrologie Pédiatrique, Centre de Référence des Maladies Rénales Héréditaires (MARHEA), Hôpital Necker-Enfants Malades, Paris, France; Inserm U983, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
Karim
K
Bouchireb
Olivia
O
Boyer
Olivier
O
Gribouval
Fabien
F
Nevo
Evelyne
E
Huynh-Cong
Vincent
V
Morinière
Raphaëlle
R
Campait
Elisabet
E
Ars
Damien
D
Brackman
Jacques
J
Dantal
Philippe
P
Eckart
Maddalena
M
Gigante
Beata S
BS
Lipska
Aurélia
A
Liutkus
André
A
Megarbane
Nabil
N
Mohsin
Fatih
F
Ozaltin
Moin A
MA
Saleem
Franz
F
Schaefer
Kenza
K
Soulami
Roser
R
Torra
Nicolas
N
Garcelon
Géraldine
G
Mollet
Karin
K
Dahan
Corinne
C
Antignac
D000328:Adult; D017668:Age of Onset; D000818:Animals; D002675:Child, Preschool; D004195:Disease Models, Animal; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012984:Software
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein
FSGS; NPHS2; podocin; steroid-resistant nephrotic syndrome