OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells

OCRL mutations are associated with both Lowe syndrome and Dent-2 disease, two rare X-linked conditions. Lowesyndromeisanoculo-cerebro-renaldisorder,whereasDent-2patientsmainlypresentrenalproximaltubulopathy. Loss of OCRL-1, a phosphoinositide-5-phosphatase, leads in Lowe patients’ fibroblasts to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) accumulation, with defects in F-actin network, a-actinin distribution and ciliogenesis, whereas fibroblasts of Dent-2 patients are still uncharacterized. To search for mechanisms linked to clinical variability observed between these twoOCRL mutation-associated pathologies, we compared dermalfibroblasts from independent patients,four affectedbyDent-2 diseaseandsixwith Lowesyndrome.For the first time, we describe that Dent-2 fibroblasts with OCRL loss-of-function (LOF) mutations exhibit decrease in actin stress fibers, appearance of punctate a-actinin signals and alteration in primary cilia formation. Interestingly, we quantified these phenotypes as clearly intermediate between Lowe and control fibroblasts, thus suggesting that levels of these defects correlate with clinical variations observed between patients with OCRL mutations. In addition, we show that Lowe and Dent-2 fibroblasts display similar PI(4,5)P2 accumulation levels. Finally, we analyzed INPP5B, a paralogous gene already reported to exhibit functional redundancy with OCRL,andreportneitherdifferencesinitsexpressionatRNAorproteinlevels,norspecificallelicvariationsbetween fibroblasts of patients. Altogether, we describe here differential phenotypes between fibroblasts from Lowe and Dent-2 patients, both associated with OCRL LOF mutations, we exclude direct roles of PI(4,5)P2 andINPP5Binthisphenotypicvariabilityandweunderlinepotentialkeyalterationsleadingtoocularandneurological clinical features in Lowe syndrome.