title: 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.
authors.affiliation: Molecular Biology Laboratory, Fundació Puigvert, Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Santín
authors.forename: Rafael
authors.initials: R
authors.lastname: García-Maset
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruíz
authors.forename: Isabel
authors.initials: I
authors.lastname: Giménez
authors.forename: Isabel
authors.initials: I
authors.lastname: Zamora
authors.forename: Antonia
authors.initials: A
authors.lastname: Peña
authors.forename: Alvaro
authors.initials: A
authors.lastname: Madrid
authors.forename: Juan A
authors.initials: JA
authors.lastname: Camacho
authors.forename: Gloria
authors.initials: G
authors.lastname: Fraga
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez-Moreno
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Cobo
authors.forename: Carmen
authors.initials: C
authors.lastname: Bernis
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Augusto Luque
authors.initials: AL
authors.lastname: de Pablos
authors.forename: Guillem
authors.initials: G
authors.lastname: Pintos
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Justa
authors.forename: Emilia
authors.initials: E
authors.lastname: Hidalgo-Barquero
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández-Llama
authors.forename: José
authors.initials: J
authors.lastname: Ballarín
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
mesh_terms: D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005923:Glomerulosclerosis, Focal Segmental / Q000151:congenital / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000151:congenital / Q000235:genetics; D013030:Spain
chemical_list: D008565:Membrane Proteins; C113267:nephrin