The molecular basis of childhood nephrotic syndrome.

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

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease