Article

Exclusion of homozygous PLCE1 (NPHS3) mutations in 69 families with idiopathic and hereditary FSGS.

Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA.
Pediatric Nephrology (Impact Factor: 2.88). 10/2008; 24(2):281-5. DOI: 10.1007/s00467-008-1025-5
Source: PubMed

ABSTRACT Focal and segmental glomerulosclerosis (FSGS) is the most common glomerular cause of end-stage kidney disease (ESKD). Although the etiology of FSGS has not been fully elucidated, recent results from the positional cloning of genes mutated in nephrotic syndromes are now beginning to provide insight into the pathogenesis of these diseases. Mutations in PLCE1/NPHS3 have recently been reported as a cause of nephrotic syndrome characterized by diffuse mesangial sclerosis (DMS) histology. One single family with a missense mutation had late onset of the disease that was characterized by FSGS. To further define the role of PLCE1 mutations in the etiology of FSGS, we performed mutational analysis in 69 families with FSGS. A total of 69 families with 231 affected individuals were examined. The median age of disease onset was 26 years (range 1-66 years). Onset of ESKD was at a median age of 35.5 years. Seven variants leading to non-synonymous changes were found, of which only two are new variants (exon 4 c.1682 G>A R561Q, exon 31 c.6518A>G K2173R). No known disease-causing mutations were identified in the families screened. PLCE1/NPHS3 mutations are not a cause of FSGS in this cohort. The absence of mutations in PLCE1/NPHS3 in this study indicates that there are additional genetic causes of FSGS and that hereditary FSGS is a heterogeneous disease. Kindreds appropriate for genome-wide screening are currently being subjected to analysis with the aim of identifying other genetic causes of FSGS.

Download full-text

Full-text

Available from: Peter J Lavin, Jul 01, 2015
0 Followers
 · 
150 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Two fully human mAbs specific for epitopes dependent on intact carboxylate groups on the C6 carbon of the mannuronic acid components of Pseudomonas aeruginosa alginate were found to promote phagocytic killing of both mucoid and nonmucoid strains as well as protection against both types of strains in a mouse model of acute pneumonia. The specificity of the mAbs for alginate was determined by ELISA and killing assays. Some strains of P. aeruginosa did not make detectable alginate in vitro, but in vivo protection against lethal pneumonia was obtained and shown to be due to rapid induction of expression of alginate in the murine lung. No protection against strains genetically unable to make alginate was achieved. These mAbs have potential to be passive therapeutic reagents for all strains of P. aeruginosa and the results document that alginate is a target for the proper type of protective Ab even when expressed at low levels on phenotypically nonmucoid strains.
    The Journal of Immunology 12/2004; 173(9):5671-8. DOI:10.4049/jimmunol.173.9.5671 · 5.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Urinary losses of macromolecules in nephrotic syndrome (NS) reflect a dysfunction of the highly permselective glomerular filtration barrier. Genetic studies of hereditary forms of NS have led to the identification of proteins playing a crucial role in slit-diaphragm signalling, regulation of actin cytoskeleton dynamics, maintenance of podocyte integrity and cell–matrix interactions. This review will focus on recent molecular and clinical findings in the field of genetics of NS, thereby providing a better understanding of the complex glomerular filtration barrier physiology.
    Human Molecular Genetics 10/2009; 18(R2):R185-94. DOI:10.1093/hmg/ddp328 · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Steroid-resistant nephrotic syndrome (SRNS) is an inherent deficiency of podocyte caused by mutations of genes encoding slit diaphragm proteins. Mutations in NPHS2, encoding podocin, have been identified as responsible for childhood-onset familial SRNS. The present study revealed the genotype of a Chinese pedigree with autosomal recessive (AR) SRNS and reported a novel disease-causing NPHS2 mutation. A Chinese pedigree with AR-SRNS was enrolled in the study. All eight exons and exon-intron boundaries of NPHS2 genes were amplified from the genomic DNA of the family members and analysed by direct sequencing. The deficient expression of the mutant protein was illustrated by indirect immunofluorescence. A compound heterozygous NPHS2 mutation (c.211C > T /c.460dupT) was found in the proband. The paternal c.211C > T is a novel point mutation, resulting in an immediate stop codon (p.Arg71X). The maternal c.460dupT is a frameshift mutation introducing an earlier stop codon (p.Phe156AspfsX10). Both mutations could be expected to lead to truncated protein of podocin. Abnormal expression and distribution of the mutated protein were also exhibited in the patient. The compound heterozygous mutation in NPHS2 may explain the development of SRNS in this family. p.Arg71X is a novel disease-causing mutation leading to a deficient expression of podocin.
    Pathology 12/2009; 41(7):661-5. DOI:10.3109/00313020903273118 · 2.62 Impact Factor