TY - JOUR
T1 - Nephrin mutations cause childhood-and adult-onset focal segmental glomerulosclerosis
AU - Santín, Sheila
AU - García-Maset, Rafael
AU - Ruíz, Patricia
AU - Giménez, Isabel
AU - Zamora, Isabel
AU - Pẽa, Antonia
AU - Madrid, Lvaro
AU - Camacho, Juan A.
AU - Fraga, Gloria
AU - Sánchez-Moreno, Ana
AU - Cobo, Maria Ngeles
AU - Bernis, Carmen
AU - Ortiz, Alberto
AU - De Pablos, Augusto Luque
AU - Pintos, Guillem
AU - Justa, Maria Luisa
AU - Hidalgo-Barquero, Emilia
AU - Fernández-Llama, Patricia
AU - Ballarín, José
AU - Ars, Elisabet
AU - Torra, Roser
PY - 2009/12/1
Y1 - 2009/12/1
N2 - 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. © 2009 International Society of Nephrology.
AB - 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. © 2009 International Society of Nephrology.
KW - Adult
KW - Congenital nephrotic syndrome of the Finnish type (CNF)
KW - Focal and segmental glomerulosclerosis (FSGS)
KW - In silico scoring system analysis
KW - NPHS1 gene
KW - Steroid-resistant nephrotic syndrome (SRNS)
U2 - 10.1038/ki.2009.381
DO - 10.1038/ki.2009.381
M3 - Article
VL - 76
SP - 1268
EP - 1276
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 12
ER -