NPHS2 variation in focal and segmental glomerulosclerosis.
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".


CONCLUSIONS
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.
Tonna
Stephen J
SJ
Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. stonna@rics.bwh.harvard.edu
Needham
Alexander
A
Polu
Krishna
K
Uscinski
Andrea
A
Appel
Gerald B
GB
Falk
Ronald J
RJ
Katz
Avi
A
Al-Waheeb
Salah
S
Kaplan
Bernard S
BS
Jerums
George
G
Savige
Judy
J
Harmon
Jennifer
J
Zhang
Kang
K
Curhan
Gary C
GC
Pollak
Martin R
MR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003928:Diabetic Nephropathies / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein