Abstract

Lowe syndrome is an X-linked condition characterized by congenital cataracts, neurological abnormalities and kidney malfunction. This lethal disease is caused by mutations in the OCRL1 gene, which encodes for the phosphatidylinositol 5-phosphatase Ocrl1. While in the past decade we witnessed substantial progress in the identification and characterization of LS patient cellular phenotypes, many of these studies have been performed in knocked-down cell lines or patient’s cells from accessible cell types such as skin fibroblasts, and not from the organs affected. This is partially due to the limited accessibility of patient cells from eyes, brain and kidneys. Here we report the preparation of induced pluripotent stem cells (iPSCs) from patient skin fibroblasts and their reprogramming into kidney cells. These reprogrammed kidney cells displayed primary cilia assembly defects similar to those described previously in cell lines. Additionally, the transcription factor and cap mesenchyme marker Six2 was substantially retained in the Golgi complex and the functional nuclear-localized fraction was reduced. These results were confirmed using different batches of differentiated cells from different iPSC colonies and by the use of the human proximal tubule kidney cell line HK2. Indeed, OCRL1 KO led to both ciliogenesis defects and Six2 retention in the Golgi complex. In agreement with Six2’s role in the suppression of ductal kidney lineages, cells from this pedigree were over-represented among patient kidney-reprogrammed cells. We speculate that this diminished efficacy to produce cap mesenchyme cells would cause LS patients to have difficulties in replenishing senescent or damaged cells derived from this lineage, particularly proximal tubule cells, leading to pathological scenarios such as tubular atrophy.

Highlights

  • The Oculo-Cerebro-Renal syndrome of Lowe (OCRL), known as Lowe syndrome (LS) is a genetic disease caused by mutations in the OCRL1 gene which encodes for an inositol 5-phosphatase (EC 3.1.3.36) [1]

  • A variety of cellular phenotypes associated with Ocrl1-deficiency have been described, including phosphatidylinositol (4, 5) bisphosphate [PI(4, 5)P2] accumulation [17,18], actin and RhoGTPase regulation abnormalities [17,19,20,21,22,23], trafficking [17,24,25,26,27] and ciliogenesis abnormalities [5,6,7,8]

  • To assess phenotype disease relevance it is necessary to ascertain whether cells from LS-affected organs display similar cellular abnormalities as those described in patient fibroblasts

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Summary

Introduction

The Oculo-Cerebro-Renal syndrome of Lowe (OCRL), known as Lowe syndrome (LS) is a genetic disease caused by mutations in the OCRL1 gene which encodes for an inositol 5-phosphatase (EC 3.1.3.36) [1]. Given the broad functional relevance of the PC, these pathological conditions are characterized by multi-organ compromise, including brain/eye/kidney abnormalities [13,14,16] These observations further highlight the potential relevance of PC phenotypes as an underlying cause of LS symptoms. Some kidney cells can be isolated and expanded from urine samples, unpredictable yields and the need of repeating such a laborious process with each patient (to capture patient variability in terms of OCRL1 mutations and genetic background/modifiers) represents a challenge. This approach is not suitable for brain- and eye-derived cell types

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