OBJECTIVES: Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations. METHODS: We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage. RESULTS: We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment. CONCLUSIONS: First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.
OBJECTIVES: Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations. METHODS: We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage. RESULTS: We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment. CONCLUSIONS: First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.
Authors: Meredith A Bostrom; W H Linda Kao; Man Li; Hanna E Abboud; Sharon G Adler; Sudha K Iyengar; Paul L Kimmel; Robert L Hanson; Susanne B Nicholas; Rebekah S Rasooly; John R Sedor; Josef Coresh; Orly F Kohn; David J Leehey; Denyse Thornley-Brown; Erwin P Bottinger; Michael S Lipkowitz; Lucy A Meoni; Michael J Klag; Lingyi Lu; Pamela J Hicks; Carl D Langefeld; Rulan S Parekh; Donald W Bowden; Barry I Freedman Journal: Am J Kidney Dis Date: 2011-11-25 Impact factor: 8.860
Authors: Yeawon Kim; Sun-Ji Park; Scott R Manson; Carlos Af Molina; Kendrah Kidd; Heather Thiessen-Philbrook; Rebecca J Perry; Helen Liapis; Stanislav Kmoch; Chirag R Parikh; Anthony J Bleyer; Ying Maggie Chen Journal: JCI Insight Date: 2017-12-07
Authors: Heon Yung Gee; Shazia Ashraf; Xiaoyang Wan; Virginia Vega-Warner; Julian Esteve-Rudd; Svjetlana Lovric; Humphrey Fang; Toby W Hurd; Carolin E Sadowski; Susan J Allen; Edgar A Otto; Emine Korkmaz; Joseph Washburn; Shawn Levy; David S Williams; Sevcan A Bakkaloglu; Anna Zolotnitskaya; Fatih Ozaltin; Weibin Zhou; Friedhelm Hildebrandt Journal: Am J Hum Genet Date: 2014-05-08 Impact factor: 11.025
Authors: Maija Suvanto; Jaakko Patrakka; Timo Jahnukainen; Pia-Maria Sjöström; Matti Nuutinen; Pekka Arikoski; Janne Kataja; Marjo Kestilä; Hannu Jalanko Journal: Clin Exp Nephrol Date: 2016-08-29 Impact factor: 2.801