Clinical variation in Lowe syndrome: what and how?

Abstract

Lowe syndrome is an X-linked disorder caused by mutations of the OCRL gene which encodes the enzyme inositol polyphosphate-5-phosphatase OCRL (Ocrl1) and is expressed in almost all body cells. Clinical characteristics involve kidney, brain, eye, muscle, bone, teeth, testes, skin and thrombocytes. Clinical phenotypes are heterogenous among families and even among affected boys in the same family. All have kidney disease varying from severe manifestations of Fanconi syndrome to only low molecular weight proteinuria, hypercalciuria and little kidney disease in the first decade of life. All develop chronic kidney disease (CKD) that typically progresses slowly and reaches stages 4-5 after the second or third decade. All have neurological dysfunction, including developmental delay, marked intellectual impairment and behavioral abnormalities; ∼50% have seizure disorder. Congenital cataracts with or without glaucoma are almost always present. Less common features are hypotonia, bone abnormalities unrelated to kidney disease, abnormal teeth, cryptorchidism, skin cysts and mild bleeding disorder. Although Lowe syndrome is a monogenic disease, genotype/phenotype correlation is difficult to establish. Ubiquitous expression and complexity of Ocrl1 function likely contribute to the elusiveness of correlation. Additionally, two diseases, Lowe syndrome and Dent disease type 2, result from mutations in the OCRL gene with some overlap in affected exons. Growing research in molecular and conformational abnormalities of Ocrl1 variants is triggering development of cell phenotype models for further study. Understanding how genotype leads to clinical phenotype has potential to provide better predictors of Lowe syndrome severity and specific therapeutic strategies for different subsets of affected patients.

Keywords: Lowe syndrome; dent disease 2; genotype; kidney; neurologic; ocrl; oculocerobrorenal; phenotype.

FIGURE 1

Schematic map of OCRL gene exons (black boxes not drawn to scale) that encode domains of the Ocrl1 protein (grey boxes) with functions of the Ocrl1 domains. Most mutations cluster in exons 8–24 for Lowe syndrome and exons 1–15 for Dent 2. Overlap with exons 8–15 may account for some of the overlap in clinical symptoms between the two diseases, although patients with OCRL mutation in the same location may have completely different clinical phenotypes (Zaniew et al., 2018; Hichri et al., 2011; Du et al., 2024; Ando et al., 2024; Akhtar et al., 2022). Function of the PH domain of the Ocrl1 protein, encoded by exons 2-5, is yet to be determined (De Sa et al., 2025). The PH domain contains a clathrin box motif, but it is not functional in the normally folded protein. The 5-phosphatase domain, encoded by exons 9–15, catalyzes dephosphorylation at the 5-position of the inositol ring in phosphoinositide lipids, especially phosphatidylinositol 4,5-bisphosphate. The ASH domain, encoded by exons 16–20, binds to Rab GTPases to guide proper targeting of Ocrl1 within cells. Alternative splicing of exon 18a between exons 18 and 19 in the OCRL gene leads to an isoform expressed primarily in the brain. The RhoGAP-like domain, encoded by exons 21–24, folds together with the ASH domain to form a functional unit that is essential for protein-protein interactions for signaling and trafficking in cells. NH2; N-terminal end of Ocrl1; PH, pleckstrin homology; ASH, ASPM-SPD2-Hydrin; RhoGAP, Rho GTPase activating; COOH; C-terminal end of Ocrl1.