Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis

Abstract

Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease.

Mutations in NPHS1 in a Chinese child with congenital nephrotic syndrome

“…The NPHS1 mutation of 3250insG, which leads to a frameshift and a truncated nephrin protein, V1084fsX1095, was previously reported and accepted as a pathological mutation (Lenk-keri et al, 1999;Santín et al, 2009;Lee et al, 2009). Santín et al (2009) considered that nonsense and frameshift mutations, which are predicted to result in a truncated protein, are classified as a severe mutation.…”

“…Santín et al (2009) considered that nonsense and frameshift mutations, which are predicted to result in a truncated protein, are classified as a severe mutation. In our study, the patient with a homozygous mutation of V1084fsX1095 presented generalized edema at six days after birth and marked hypoalbuminemia, with a serum albumin level of 4.6 g/L, suggesting that severe mutations cause a severe clinical phenotype.…”

Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

“…The high percentage of NPHS2 missense variants represents a diagnostic challenge because in some cases it is difficult to differentiate between a disease-causing mutation and a neutral variant. We describe here an in silico sequence variant classification strategy for the NPHS2 amino acid substitutions based on the combination of different approaches previously reported for other genes (30,41,42), which takes into account (1) the analysis of control chromosomes, (2) the cosegregation with the disease in a family, (3) the biophysical and biochemical difference between wild-type and mutant amino acids (28), (4) the evolutionary conservation of the amino acid residue in orthologs (29,43,44), and (5) software that uses in silico predictors of pathogenic effect [Polyphen (45), SIFT (46)] and splice site [Neural Network (47)]. The accuracy of this in silico analysis was tested using previously described and classified podocin-amino acid substitutions.…”

Steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at <i>NPHS1</i> and <i>ADCK4</i> genes in two Chinese siblings

“…Classically, mutations in the NPHS1 and NPHS2 genes have been distinguished by their implications in familial congenital (onset at birth to 3 month) and in childhood-onset (later than 3 month) cases, respectively (5,11). Furthermore, it has recently been shown that mutations in NPHS1 also account for a nonnegligible proportion of infantile, childhood and adult-onset SRNS cases (12)(13)(14). ADCK4 gene, which located on chromosome 19q13.2 and encodes the aarF domain containing kinase 4, is now well-known as a single-gene cause of SRNS (15)(16)(17).…”