Koziell, A.B.; (2007) The molecular basis of childhood nephrotic syndrome. Doctoral thesis , University of London.

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Abstract

Childhood nephrotic syndrome results from massive leakage of protein into the urine, a low plasma albumin and oedema. Disease may be kidney-specific, occur as part of a malformation syndrome, or may complicate systemic diseases such as diabetes mellitus. Despite the apparent heterogeneity, the underlying defect is loss of the normal permselective characteristics of the glomerular filtration barrier (GFB). Clues for a molecular basis came from observation of occasional autosomal dominant or recessive inheritance, and the detection of WT1 mutations in Denys Drash syndrome (DDS), a triad of intersex, nephrotic syndrome and Wilms' tumour (Pelletier et al, 1991). The role of three glomerular genes WTl, NPHS1 and NPHS2 in the pathogenesis of glomerular protein leak was investigated. WTl mutations were not detected in non- syndromic diffuse mesangial sclerosis (DMS) and focal segmental glomerulosclerosis (FSGS), despite their association with DDS. However, subsequent analysis established that WTl mutations cause Frasier syndrome, a triad of FSGS, intersex and gonadoblastoma, by reversing the normal +(KTS)/-(KTS) WTl isoform ratio. Unfortunately, yeast 2-hybrid screens failed to ascertain any WTl protein binding partners with clear roles in glomerular function, and through which the effects of mutations might be mediated. A wide range of NPHS1 mutations was detected in Finnish type congenital nephrotic syndrome (CNF) in non-Finns, and a novel mild CNF phenotype described. NPHS2 mutations affected some CNF cases, and an overlap in the NPHS1/NPHS2 mutation spectrum was confirmed by the discovery of a unique di-genic inheritance of mutations. This modified the phenotype from CNF to congenital FSGS, providing the first evidence for a functional inter-relationship between these genes. Finally, disrupted protein-DNA binding to an area of the NPHS1 promoter containing a G->C base substitution was identified, suggesting the location of a transcription factor binding site and underscoring the importance of appropriate transcriptional control of NPHS1 for correct gene function.

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