Genotypic and Phenotypic Features of Both NPHS1 and NPHS2 Genes in Infantile Nephrotic Syndrome and Prognostic Effect of E117K Polymorphism in NPHS1 Gene

WOS: 000471326300002Background: Infantile nephrotic syndrome (INS) refers to disease that is present after the first three months of life up to one year of age. There is genetic heterogeneity and genotype-phenotype correlation is not clear. Objectives: The focus of the present study was to analyze genotypic and phenotypic features of both NPHS1 and NPHS2 genes in INS. Methods: Clinical data, mutational analysis, histology, treatments, and outcomes of 48 children with NS are evaluated. A direct sequencing of NPHS1 gene and NPHS2 gene was performed. Patients were classified into 3 groups; group 1: cases having only NPHS1 mutation; group 2: cases with only NPHS2 mutation; group 3: cases without any mutation. Results: The mean age at onset of the disease was 8.7 +/- 2.3 months, and mean follow-up time was 8.3 years. Seven familial and 41 sporadic cases of INS were found. Kidney biopsy was performed in 45 out of 48 patients and pathological investigations revealed focal segmental glomerulosclerosis in 29 (65%), IgM nephropathy in 6 (13%), and minimal change disease in 10 patients (22%). There were 5 (10.4%) cases in groups (patients having only mutations of NPHS1)and 13 cases (27%) in group 2 (patients having only mutations of NPHS2). Thirty cases (62.5%) had neither NPHS1 nor NPHS2 mutation (group 3). Conclusions: The genotypic and phenotypic features of INS were demonstrated. We found that INS with podocin mutation has poor prognosis according to exonal distribution. NPHS1 mutations caused a severe disease but with a more favorable prognosis

Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations.

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal recessive disorder that is caused by mutations in the recently discovered nephrin gene, NPHS1 (AF035835). The disease, which belongs to the Finnish disease heritage, exists predominantly in Finland, but many cases have been observed elsewhere in Europe and North America. The nephrin gene consists of 29 exons spanning 26 kb in the chromosomal region 19q13.1. In the present study, the genomic structure of the nephrin gene was analyzed, and 35 NPHS1 patients were screened for the presence of mutations in the gene. A total of 32 novel mutations, including deletions; insertions; nonsense, missense, and splicing mutations; and two common polymorphisms were found. Only two Swedish and four Finnish patients had the typical Finnish mutations: a 2-bp deletion in exon 2 (Finmajor) or a nonsense mutation in exon 26 (Finminor). In seven cases, no mutations were found in the coding region of the NPHS1 gene or in the immediate 5'-flanking region. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin

Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.

PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region

Turnover of amyloid precursor protein family members determines their nuclear signaling capability

The amyloid precursor protein (APP) as well as its homologues, APP-like protein 1 and 2 (APLP1 and APLP2), are cleaved by α-, β-, and γ-secretases, resulting in the release of their intracellular domains (ICDs). We have shown that the APP intracellular domain (AICD) is transported to the nucleus by Fe65 where they jointly bind the histone acetyltransferase Tip60 and localize to spherical nuclear complexes (AFT complexes), which are thought to be sites of transcription. We have now analyzed the subcellular localization and turnover of the APP family members. Similarly to AICD, the ICD of APLP2 localizes to spherical nuclear complexes together with Fe65 and Tip60. In contrast, the ICD of APLP1, despite binding to Fe65, does not translocate to the nucleus. In addition, APLP1 predominantly localizes to the plasma membrane, whereas APP and APLP2 are detected in vesicular structures. APLP1 also demonstrates a much slower turnover of the full-length protein compared to APP and APLP2. We further show that the ICDs of all APP family members are degraded by the proteasome and that the N-terminal amino acids of ICDs determine ICD degradation rate. Together, our results suggest that different nuclear signaling capabilities of APP family members are due to different rates of full-length protein processing and ICD proteasomal degradation. Our results provide evidence in support of a common nuclear signaling function for APP and APLP2 that is absent in APLP1, but suggest that APLP1 has a regulatory role in the nuclear translocation of APP family ICDs due to the sequestration of Fe65