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BMC Nephrology
Published in: BMC Nephrology 1/2008

Open Access 01-12-2008 | Research article

NPHS2variation in focal and segmental glomerulosclerosis

Authors: Stephen J Tonna, Alexander Needham, Krishna Polu, Andrea Uscinski, Gerald B Appel, Ronald J Falk, Avi Katz, Salah Al-Waheeb, Bernard S Kaplan, George Jerums, Judy Savige, Jennifer Harmon, Kang Zhang, Gary C Curhan, Martin R Pollak

Published in: BMC Nephrology | Issue 1/2008

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Abstract

Background

Focal and segmental glomerulosclerosis (FSGS) is the most common histologic pattern of renal injury seen in adults with idiopathic proteinuria. Homozygous or compound heterozygous mutations in the podocin gene NPHS2 are found in 10–30% of pediatric cases of steroid resistant nephrosis and/or FSGS.

Methods

We studied the spectrum of genetic variation in 371 individuals with predominantly late onset FSGS (mean age of onset 25 years) by analysis of DNA samples.

Results

We identified 15 non-synonymous alleles that changed the amino acid sequence in 63 of the subjects screened (17%). Eight of these (p.R138Q, p.V180M, p.R229Q, p.E237Q, p.A242V, p.A284V, p.L327F and the frameshift 855–856 delAA) are alleles previously reported to cause FSGS in either the homozygous or compound heterozygous states, while the remaining 7 (p.R10T, p.V127W, p.Q215X, p.T232I, p.L270F, p.L312V and the frameshift 397delA) are novel alleles that have not been demonstrated previously. Twelve individuals of the 371 (3.2%) screened had two likely disease-causing NPHS2 alleles, present in either a homozygous or compound heterozygous state. We genotyped the two most common of the non-synonymous NPHS2 alleles (p.A242V and p.R229Q) identified by resequencing in participants from the Nurses' Health Study and also genotyped p.R229Q in 3 diabetic cohorts. We found that the presence of either of these variants does not significantly alter the risk of albuminuria in the Nurses' Health participants, nor does p.R229Q associate with "diabetic nephropathy".

Conclusion

NPHS2 mutations are a rare cause of FSGS in adults. The most common non-synonymous NPHS2 variants, p.R229Q and p.A242V, do not appear to alter the risk of proteinuria in the general population nor does p.R229Q associate with measures of kidney dysfunction in diabetic individuals. Our results help clarify the frequency of FSGS-causing NPHS2 mutations in adults and broaden our understanding of the spectrum of NPHS2 mutations that lead to human disease.
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Metadata
Title
NPHS2variation in focal and segmental glomerulosclerosis
Authors
Stephen J Tonna
Alexander Needham
Krishna Polu
Andrea Uscinski
Gerald B Appel
Ronald J Falk
Avi Katz
Salah Al-Waheeb
Bernard S Kaplan
George Jerums
Judy Savige
Jennifer Harmon
Kang Zhang
Gary C Curhan
Martin R Pollak
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2008
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/1471-2369-9-13

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