Abstract
BackgroundLowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases.MethodsHere, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed.ResultsSurprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm.ConclusionTaken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.
Highlights
The oculocerebrorenal syndrome of Lowe, known as Lowe syndrome, is a rare X-linked disorder caused by Bristol, UK 4 Division of Molecular and Cellular Function, School of BiologicalSciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK 5 Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester Academic Health Science Centre, Manchester University Hospital NHS Foundation Trust, Manchester, UK mutations in the OCRL gene, which encodes for a type II inositol polyphosphate 5-phosphatase [1]
The renal phenotypes associated with Lowe syndrome are observed in Dent disease, which is an X-linked proximal tubulopathy characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and progressive chronic kidney disease (CKD) [3, 9, 10]
We report the case of a patient who presented with nephrotic-range proteinuria and focal segmental glomerulosclerosis (FSGS)
Summary
The renal phenotypes associated with Lowe syndrome are observed in Dent disease, which is an X-linked proximal tubulopathy characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and progressive CKD [3, 9, 10]. Mild or sub-clinical extra-renal manifestations have been reported with Dent-2 disease and include peripheral cataracts, intellectual disability and short stature [5, 8, 16]. This overlap of clinical phenotypes between Lowe syndrome and Dent-2 disease is indicative of the heterogeneity of OCRL mutations. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases
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