Abstract
The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene (OCRL) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.
Highlights
The classic form of the oculocerebrorenal syndrome of Lowe (OMIM #309000), first described by Lowe et al in 1952 [1], is characterized by the triad of congenital cataracts, severe intellectual impairment, and renal tubular dysfunction with slowly progressive renal failure [2, 3]
We provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1
Lowe syndrome is caused by variants in the OCRL gene on chromosome Xq25-26, which encodes OCRL-1, an inositol polyphosphate 5-phosphatase [4]
Summary
The classic form of the oculocerebrorenal syndrome of Lowe (OMIM #309000), first described by Lowe et al in 1952 [1], is characterized by the triad of congenital cataracts, severe intellectual impairment, and renal tubular dysfunction with slowly progressive renal failure [2, 3]. As already noted in this review, there is overlap in clinical signs between patients with Lowe syndrome and those with Dent-2 disease, with the latter possibly presenting with extrarenal features of Lowe syndrome This clinical observation is supported by a recent study on fibroblasts from patients with Lowe syndrome and Dent-2 disease in which Montjean et al [86] demonstrated an intermediate phenotype of Dent-2 fibroblasts in terms of the Factin network, alpha-actinin, and primary cilia. Whether this mechanism does explain the phenotypic differences between patients with Dent-2 disease and those with Lowe syndrome as Montjean et al observed identical expression of OCRL and of INPP5B at the RNA and protein levels in fibroblasts from both Dent-2 and Lowe syndrome patients [86]
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