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Review
. 2016 Dec;31(12):2201-2212.
doi: 10.1007/s00467-016-3343-3. Epub 2016 Mar 24.

The oculocerebrorenal syndrome of Lowe: an update

Arend Bökenkamp  1 , Michael Ludwig  2
Affiliations
Review

The oculocerebrorenal syndrome of Lowe: an update

Arend Bökenkamp et al. Pediatr Nephrol. 2016 Dec.

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.

Keywords: Cognitive and behavioral impairment; Congenital cataract; Inositol-polyphosphate 5-phosphatase; OCRL gene; Oculocerebrorenal syndrome; Proximal tubulopathy; Renal Fanconi syndrome.

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Conflict of interest statement

Compliance with ethical standards Conflict of interests The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Pathogenesis of low-molecular-weight (LMW) proteinuria in Lowe syndrome. LMW proteins (filled circles) are internalized after binding to megalin (helices) on the brush border of proximal tubular cells. a In the wild-type, the megalin–LMW protein complex in the endosome dissociates at low pH, followed by the recycling of megalin to the cell surface and delivery of the LMW proteins to lysosomes for degradation. b In Lowe syndrome/Dent-2 disease, megalin trafficking to the cell surface is impaired. Due to the aberrant accumulation of actin at the endosomal membrane, megalin is retained in the endosome and mis-sorted to the lysosome instead of being recycled to the brush border via recycling tubules (modified from Mehta et al. [33] with permission)
Fig. 2
Fig. 2
Structure and function of phosphoinositide (4,5)P2 5-phosphatase (OCRL-1). Black boxes Exome structure of the OCRL gene, including the alternatively spliced exon 18a, shaded boxes domains/binding sites of the OCRL-1 protein, dashed boxes functions related to the different domains, text in italics intracellular processes involving OCRL-1. PtdIns Phosphoinositide, PH N-terminal pleckstrin homology domain, 5-phosphatase 5-phosphatase domain, ASH ASPM–SPD2–Hydin domain, RhoGap C-terminal (catalytically non-active) Rho GTPase activating-like domain
Fig. 3
Fig. 3
Subcellular localization of OCRL-1. Cartoon summarizing subcellular expression of OCRL-1 (hexagones). TGN Trans-Golgi network, MVB multivesicular body (modified from Mehta et al. [33], with permission)
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