title: NPHS2 variation in focal and segmental glomerulosclerosis.
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".
  
  
  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.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. stonna@rics.bwh.harvard.edu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tonna
authors.forename: Alexander
authors.initials: A
authors.lastname: Needham
authors.forename: Krishna
authors.initials: K
authors.lastname: Polu
authors.forename: Andrea
authors.initials: A
authors.lastname: Uscinski
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Appel
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.forename: Avi
authors.initials: A
authors.lastname: Katz
authors.forename: Salah
authors.initials: S
authors.lastname: Al-Waheeb
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Kaplan
authors.forename: George
authors.initials: G
authors.lastname: Jerums
authors.forename: Judy
authors.initials: J
authors.lastname: Savige
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harmon
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Gary C
authors.initials: GC
authors.lastname: Curhan
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: 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
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein