Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome.
OBJECTIVE
To date, very few cases with adult-onset focal segmental glomerulosclerosis (FSGS) carrying NPHS2 variants have been described, all of them being compound heterozygous for the p.R229Q variant and one pathogenic mutation.


METHODS
Mutation analysis was performed in 148 unrelated Spanish patients, of whom 50 presented with FSGS after 18 years of age. Pathogenicity of amino acid substitutions was evaluated through an in silico scoring system. Haplotype analysis was carried out using NPHS2 single nucleotide polymorphism and microsatellite markers.


RESULTS
Compound heterozygous or homozygous NPHS2 pathogenic mutations were identified in seven childhood-onset steroid-resistant nephrotic syndrome (SRNS) cases. Six additional cases with late childhood- and adult-onset SRNS were compound heterozygotes for p.R229Q and one pathogenic mutation, mostly p.A284V. p.R229Q was more frequent among SRNS cases relative to controls (odds ratio=2.65; P=0.02). Significantly higher age at onset of the disease and slower progression to ESRD were found in patients with one pathogenic mutation plus the p.R229Q variant in respect to patients with two NPHS2 pathogenic mutations.


CONCLUSIONS
NPHS2 analysis has a clinical value in both childhood- and adult-onset SRNS patients. For adult-onset patients, the first step should be screening for p.R229Q and, if positive, for p.A284V. These alleles are present in conserved haplotypes, suggesting a common origin for these substitutions. Patients carrying this specific NPHS2 allele combination did not respond to corticoids or immunosuppressors and showed FSGS, average 8-year progression to ESRD, and low risk for recurrence of FSGS after kidney transplant.
Fundació Puigvert, Cartagena 340-350, 08025 Barcelona, Spain.
Sheila
S
Santín
Bárbara
B
Tazón-Vega
Irene
I
Silva
María Ángeles
MÁ
Cobo
Isabel
I
Giménez
Patricia
P
Ruíz
Rafael
R
García-Maset
José
J
Ballarín
Roser
R
Torra
Elisabet
E
Ars
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics; D016030:Kidney Transplantation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain; D013256:Steroids / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D013256:Steroids