Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis

Emilie Song,Daniel Neely,Cathleen Walnuss,Dan Spandau,Maria Lim,Yang Sun,Na Luo,Alireza Ghaffarieh,Jorge A Alvarado

doi:10.1038/s41598-017-01447-3

Abstract

Mutations in the OCRL1 gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and neurological impairments. OCRL1 encodes an inositol polyphosphate 5-phosphatase which preferentially dephosphorylates phosphatidylinositide 4,5 bisphosphate (PI(4,5)P2). We have identified two novel mutations in two unrelated Lowe syndrome patients with congenital glaucoma. Novel deletion mutations are detected at c.739-742delAAAG in Lowe patient 1 and c.1595-1631del in Lowe patient 2. End stage glaucoma in patient 2 resulted in the enucleation of the eye, which on histology demonstrated corneal keloid, fibrous infiltration of the angle, ectropion uvea, retinal gliosis, and retinal ganglion cell loss. We measured OCRL protein levels in patient keratinocytes and found that Lowe 1 patient cells had significantly reduced OCRL protein as compared to the control keratinocytes. Genotype-phenotype correlation of OCRL1 mutations associated with congenital glaucoma revealed clustering of missense and deletion mutations in the 5-phosphatase domain and the RhoGAP-like domain. In conclusion, we report novel OCRL1 mutations in Lowe syndrome patients and the corresponding histopathologic analysis of one patient’s ocular pathology.

Highlights

The defective gene OCRL1 is located on Xq26.1 and encodes an inositol polyphosphate 5-phosphatase; its substrates include phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3)[13,14,15,16,17]
Patient 1 (Lowe 1), who has a known history of affected family members (Fig. 1A), presented at 14 days of age with no fix/follow, elevated intraocular pressure (IOP; right eye 31 mmHg, left eye 29 mmHg), corneal edema with Haab striae, and dense bilateral cataracts (Table 1)
Lowe 1 presented with proximal renal tubular acidosis, proteinuria, Dandy Walker Syndrome, congenital muscular dystrophy, developmental delays, low phosphatidylinositol bisphosphate phosphatase (0.3 mmol/min/mg protein [normal range: 2–9]) and keratinocytes with cell growth defects

Summary

Introduction

The defective gene OCRL1 is located on Xq26.1 and encodes an inositol polyphosphate 5-phosphatase; its substrates include phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3)[13,14,15,16,17]. Most of the disease-causing mutations are located either in the phosphatase domain or the c-terminal RhoGAP domain, which may result in the loss of protein due to the lack of expression or degradation as a consequence of misfolding leading to accumulations of phosphoinositide substrates[7, 18,19,20,21,22]. We identified two new deletion mutations in two Lowe syndrome patients with congenital glaucoma and discuss the clinical-pathologic correlation in a patient with end-stage glaucoma

Methods

Results

Conclusion