Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS).
BACKGROUND
Recessive mutations in the NPHS1 gene encoding nephrin account for approximately 40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons.


METHODS
We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS.


RESULTS
We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (approximately 51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin.


CONCLUSIONS
Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatment.
Schoeb
Dominik S
DS
Department of Pediatrics, University of Michigan, 1150 W. Medical Center Drive Drive, Ann Arbor, MI, USA.
Chernin
Gil
G
Heeringa
Saskia F
SF
Matejas
Verena
V
Held
Susanne
S
Vega-Warner
Virginia
V
Bockenhauer
Detlef
D
Vlangos
Christopher N
CN
Moorani
Khemchand N
KN
Neuhaus
Thomas J
TJ
Kari
Jameela A
JA
MacDonald
James
J
Saisawat
Pawaree
P
Ashraf
Shazia
S
Ovunc
Bugsu
B
Zenker
Martin
M
Hildebrandt
Friedhelm
F
D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D005838:Genotype; D014943:Global Health; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011379:Prognosis
D008565:Membrane Proteins; C113267:nephrin