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Ozaltin, F, Ibsirlioglu, T, Taskiran, EZ, Baydar, DE, Kaymaz, F, Buyukcelik, M, Kilic, BD, Balat, A, Iatropoulos, P, Asan, E, Akarsu, NA, Schaefer, F, Yilmaz, E, Bakkaloglu, A and PodoNet Consortium (2011) Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am. J. Hum. Genet. 89:139-47


Idiopathic nephrotic syndrome (INS) is a genetically heterogeneous group of disorders characterized by proteinuria, hypoalbuminemia, and edema. Because it typically results in end-stage kidney disease, the steroid-resistant subtype (SRNS) of INS is especially important when it occurs in children. The present study included 29 affected and 22 normal individuals from 17 SRNS families; genome-wide analysis was performed with Affymetrix 250K SNP arrays followed by homozygosity mapping. A large homozygous stretch on chromosomal region 12p12 was identified in one consanguineous family with two affected siblings. Direct sequencing of protein tyrosine phosphatase receptor type O (PTPRO; also known as glomerular epithelial protein-1 [GLEPP1]) showed homozygous c.2627+1G>T donor splice-site mutation. This mutation causes skipping of the evolutionarily conserved exon 16 (p.Glu854_Trp876del) at the RNA level. Immunohistochemistry with GLEPP1 antibody showed a similar staining pattern in the podocytes of the diseased and control kidney tissues. We used a highly polymorphic intragenic DNA marker-D12S1303-to search for homozygosity in 120 Turkish and 13 non-Turkish individuals in the PodoNet registry. This analysis yielded 17 candidate families, and a distinct homozygous c.2745+1G>A donor splice-site mutation in PTPRO was further identified via DNA sequencing in a second Turkish family. This mutation causes skipping of exon 19, and this introduces a premature stop codon at the very beginning of exon 20 (p.Asn888Lysfs*3) and causes degradation of mRNA via nonsense-mediated decay. Immunohistochemical analysis showed complete absence of immunoreactive PTPRO. Ultrastructural alterations, such as diffuse foot process fusion and extensive microvillus transformation of podocytes, were observed via electron microscopy in both families. The present study introduces mutations in PTPRO as another cause of autosomal-recessive nephrotic syndrome.


PubMed PMC3135805 Online version:10.1016/j.ajhg.2011.05.026


Adolescent; Age of Onset; Amino Acid Sequence; Child; Child, Preschool; Chromosomes, Human, Pair 12; Codon, Nonsense/genetics; Consanguinity; Exons; Female; Genes, Recessive; Genome-Wide Association Study/methods; Homozygote; Humans; Male; Molecular Sequence Data; Nephrotic Syndrome/congenital; Nephrotic Syndrome/genetics; Pedigree; Polymorphism, Single Nucleotide; RNA Splice Sites; Receptor-Like Protein Tyrosine Phosphatases, Class 3/genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status



GO:0032835: glomerulus development

ECO:0000315: mutant phenotype evidence used in manual assertion


Seeded From UniProt



See also


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