nephrin and Denys-Drash-Syndrome

Great progress has been made of late in understanding the mechanisms of proteinuria, the structure and function of the slit diaphragm, and the genetic background of congenital nephrotic syndromes in new borns and infants. This paper presents recent achievements of molecular genetics in unraveling the causes of inherited disorders, e.g. Finnish-type nephrotic, Denys-Drash and Frasier's syndromes, as well as sporadic focal-segmental glomerulosclerosis. A change in the routine policy used in evaluating the causes of childhood nephrotic syndrome is discussed.

Topics: Actinin; Denys-Drash Syndrome; Frasier Syndrome; Humans; Infant; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mutation; Nephrotic Syndrome; Proteinuria; WT1 Proteins

Neonatal-onset Denys-Drash syndrome (NODDS) is a distinctive clinical entity and has a poor renal and life outcome. Early diagnosis of NODDS is important for managing disorders of sexual development and determining assigned gender. Although patients with NODDS and congenital nephrotic syndrome of the Finnish type (CNF) present with nephrotic syndrome in neonatal life or infancy, the clinical course of NODDS and factors distinguishing these diseases at onset is unknown.. We performed a retrospective cohort study of patients with NODDS and CNF between 1997 and 2017. Patients with nephrotic syndrome and WT1 or NPHS1 mutations with neonatal onset (within 30 days) were eligible.. We studied eight patients with NODDS and 15 with CNF. The median serum creatinine level at onset in the NODDS group was significantly higher (1.85 mg/dL) than that in the CNF group (0.15 mg/dL; P = 0.002). The median placental/fetal weight ratio in the NODDS and CNF group was 41.8% and 21.0%, respectively (P = 0.001). Kaplan-Meier analysis showed that the median number of days for progression to ESRD from onset in the NODDS and CNF groups was 6 and 910 days, respectively (P < 0.001). All patients in the NODDS group were alive at follow-up. Only one patient in the CNF group died of cardiac complications during follow-up.. CNS, renal dysfunction at onset, and a relatively large placenta are prominent signs of NODDS. Prognosis for patients with NODDS is satisfactory if appropriate and active management is performed.

Topics: Adolescent; Age of Onset; Child; Child, Preschool; Denys-Drash Syndrome; Disease Progression; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Kidney Failure, Chronic; Membrane Proteins; Mutation; Nephrotic Syndrome; Phenotype; Renal Dialysis; Retrospective Studies; Risk Factors; Tokyo; WT1 Proteins

The aim of the study was to present our experience in treating children with genetic forms of nephrotic syndrome and diagnosing these diseases. We retrospectively reviewed the clinical data, mutational analyses, histopathological features, treatment modalities, and outcome of 26 consecutive children (20 families) suffering from congenital and/or steroid-resistant nephrotic syndrome who were assessed by genetic analysis. Ten out of 26 children (38%) had congenital nephrotic syndrome, 4/26 (15%) had infantile nephrotic syndrome, 10/26 (38%) had late-onset nephrotic syndrome, and 2/26 (9%) had asymptomatic proteinuria. We detected a mutation in 21/26 (81%) patients and in 15/20 (75%) families. NPHS1 mutation analyses were positive in 4/20 (20%), NPHS2 mutations in 4/20 (20%), WT1 mutations in 4/20 (20%), and PLCE1 mutations in 3/20 (15%) families. NPHS1 and PLCE1 mutations were solely found in patients with the earliest onset. The majority of patients, especially those with early onset of nephrotic syndrome, had serious adverse events related to the nephrotic status, and 19/26 (73%) reached end-stage renal failure at a median age of 27 months. Genetic forms of nephrotic syndrome comprise a heterogeneous group of genetic mutations. The progression toward end-stage renal failure is the rule but is highly variable between patients.

Topics: Adolescent; Age of Onset; Belgium; Child; Child, Preschool; Denys-Drash Syndrome; Female; Frasier Syndrome; Humans; Infant; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Male; Membrane Proteins; Nephrotic Syndrome; Phosphoinositide Phospholipase C; Proteinuria; Retrospective Studies; WT1 Proteins

Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is glomerulosclerosis, the pathobiology of which is unclear. To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]). Kidney development was normal in Wt1(+/R394W) heterozygotes. However, by 4 months of age 100% of male heterozygotes displayed proteinuria and glomerulosclerosis characteristic of DDS patients. This phenotype was observed in an MF1 background but not in a mixed B6/129 background, suggestive of the action of a strain-specific modifying gene(s). WT1 encodes a nuclear transcription factor, and the R394W mutation is known to impair this function. Therefore, to investigate the mechanism of Wt1 R394W-induced renal failure, the expression of genes whose deletion leads to glomerulosclerosis (NPHS1, NPHS2, and CD2AP) was quantitated. In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months. Expression of CD2AP was not changed at birth but was significantly upregulated at 2 and 4 months. Podocalyxin was downregulated by 20% in newborn kidneys but not in kidneys at later ages. Two other genes implicated in glomerulosclerosis, TGFB1 and IGF1, were upregulated at 2 months and at 2 and 4 months, respectively. It is not clear whether the significant alterations in gene expression are a cause or a consequence of the disease process. However, the data do suggest that Wt1 R394W-induced glomerulosclerosis may be independent of downregulation of the genes for NPHS1, NPHS2, CD2AP, and podocalyxin and may involve other genes yet to be implicated in renal failure. The Wt1(R394W) mouse recapitulates the pathology and disease progression observed in patients carrying the same mutation, and the mutation is completely penetrant in male animals. Thus, it will be a powerful and biologically relevant model for investigating the pathobiology of the earliest events in glomerulosclerosis.

Topics: Adaptor Proteins, Signal Transducing; Animals; Base Sequence; Cell Division; Cytoskeletal Proteins; Denys-Drash Syndrome; Disease Models, Animal; DNA; Female; Gene Expression; Genes, Wilms Tumor; Glomerulosclerosis, Focal Segmental; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Phenotype; Point Mutation; Proteins; Renal Insufficiency; Species Specificity