Browsing by Author "Antignac, Corinne"

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    Analysis of recessive CD2AP and ACTN4 mutations in steroid-resistant nephrotic syndrome
    (2010) Benoit, Genevieve; Machuca, Eduardo; Nevo, Fabien; Gribouval, Olivier; Lepage, David; Antignac, Corinne
    Mutations in podocyte genes have been identified in patients with steroid-resistant nephrotic syndrome (SRNS). Point mutations in the ACTN4 gene cause an autosomal dominant form of human focal segmental glomerular sclerosis (FSGS); however, reports of CD2AP mutations remain scarce. Based on the phenotype of Actn4 and Cd2ap null mice, we aimed to define the role of recessive CD2AP and ACTN4 mutations in a cohort of children with SRNS for which NPHS1, NPHS2, and PLCE1 mutations had been previously excluded. CD2AP and ACTN4 mutational analysis was performed in 42 children from 35 unrelated families. The median age of disease onset was 20 (range 0-102) months. Sixteen patients reached end-stage kidney disease at a median age of 84 (range 4-161) months. Renal histology showed FSGS lesions and minimal glomerular changes in 49% and 20% of patients, respectively. Microsatellite marker analysis excluded linkage to the CD2AP locus in 26 families and to the ACTN4 locus in 31 families. No disease-causing mutations were identified in the remaining families. Recessive CD2AP and ACTN4 mutations are rare in children with SRNS. The absence of mutations in this study suggests that there are other genetic causes of SRNS that still need to be identified.
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    Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant
    (ELSEVIER SCIENCE INC, 2009) Machuca, Eduardo; Hummel, Aurelie; Nevo, Fabien; Dantal, Jacques; Martinez, Frank; Al Sabban, Essam; Baudouin, Veronique; Abel, Laurent; Gruenfeld, Jean Pierre; Antignac, Corinne
    Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients, along with further NPHS2 mutation analysis in those carrying the variant.
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    Genotype-Phenotype Correlations in Non-Finnish Congenital Nephrotic Syndrome
    (AMER SOC NEPHROLOGY, 2010) Machuca, Eduardo; Benoit, Genevieve; Nevo, Fabien; Tete, Marie Josephe; Gribouval, Olivier; Pawtowski, Audrey; Brandstrom, Per; Loirat, Chantal; Niaudet, Patrick; Gubler, Marie Claire; Antignac, Corinne
    Mutations in NPHS1, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in NPHS2, which encodes podocin, are typically responsible for childhood-onset steroid-resistant nephrotic syndrome in European populations. Genotype phenotype correlations are not well understood in non-Finnish patients. We evaluated the clinical presentation, kidney histology, and disease progression in non-Finnish CNS cases by mutational screening in 107 families (117 cases) by sequencing the entire coding regions of NPHS1, NPHS2, PLCE1, WT1, LAMB2, PDSS2, C002, and NEPH1. We found that CNS describes a heterogeneous group of disorders in non-Finnish populations. We identified nephrin and podocin mutations in most families and only rarely found mutations in genes implicated in other hereditary forms of NS. In approximately 20% of cases, we could not identify the underlying genetic cause. Consistent with the major role of nephrin at the slit diaphragm, NPHS1 mutations associated with an earlier onset of disease and worse renal outcomes than NPHS2 mutations. Milder cases resulting from mutant NPHS1 had either two mutations in the cytoplasmic tail or two missense mutations in the extracellular domain, including at least one that preserved structure and function. In addition, we extend the spectrum of known NPHS1 mutations by describing long NPHS1 deletions. In summary, these data demonstrate that CNS is not a distinct clinical entity in non-Finnish populations but rather a clinically and genetically heterogeneous group of disorders