title: NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.
abstract: Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro-translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.
authors.affiliation: Department of Laboratory Medicine, University of Tokushima, Tokushima, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tsukaguchi
authors.forename: Akulapalli
authors.initials: A
authors.lastname: Sudhakar
authors.forename: Tu Cam
authors.initials: TC
authors.lastname: Le
authors.forename: Trang
authors.initials: T
authors.lastname: Nguyen
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Schwimmer
authors.forename: Asher D
authors.initials: AD
authors.lastname: Schachter
authors.forename: Esteban
authors.initials: E
authors.lastname: Poch
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Abreu
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Appel
authors.forename: Aparecido B
authors.initials: AB
authors.lastname: Pereira
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D019943:Amino Acid Substitution; D001483:Base Sequence; D002648:Child; D005006:Ethnicity; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein