Genetics of Lowe Oculocerebrorenal Syndrome

Abstract

The classic form of the oculocerebrorenal syndrome of Lowe is a rare X‐chromosomal recessive disease characterised by congenital cataract, severe muscle hypotonia and mental retardation as well as slowly progressive renal failure. It is due to mutations in the OCRL gene encoding an inositol polyphosphate 5‐phosphatase playing a central role in gene expression, cytokinesis, cell motility, actin cytoskeleton remodelling, membrane trafficking and cell signalling. A milder variant of Lowe syndrome – also caused by OCRL mutations – is Dent‐2 disease, where renal symptoms predominate. More than 200 different OCRL mutations have been described. There is no clear genotype–phenotype correlation, yet mutations in exons 1–7 are mostly associated with a Dent phenotype while Lowe syndrome usually involves gross deletions or mutations in exons 8–23.

Key Concepts

  • Lowe syndrome is a very severe hereditary multisystem disease due to OCRL gene mutations.
  • Dent‐2 disease is a mild form of Lowe syndrome.
  • There is no clear genotype–phenotype correlation in classical Lowe syndrome.
  • OCRL mutations are spread across the entire gene and there are no hotspots.
  • In about 20% of cases of Lowe syndrome, no mutation in OCRL can be found.
  • In about one‐third Lowe syndrome is the result of a de novo mutation.

Keywords: congenital cataract; cognitive and behavioural impairment; Dent‐2 disease; OCRL gene; OCRL‐1 protein; oculocerebrorenal syndrome; Phosphoinositides; PtdIns(4,5)P2 5‐phosphatase; proximal tubulopathy; renal Fanconi syndrome

Figure 1. Subcellular localisation of OCRL‐1. Cartoon summarising the subcellular expression of OCRL‐1 (hexagones). TGN; trans‐Golgi network, MVB; multivesicular body. Source: https://onlinelibrary.wiley.com/doi/full/10.1111/tra.12160. Licensed under CC by 3.0.
Figure 2. Pathogenesis of LMW proteinuria in Lowe syndrome. Low‐molecular‐weight proteins (LMWP, filled circles) are internalised after binding to megalin (helices) on the brush border of proximal tubular cells. In the wild‐type (a), the megalin‐LMWP complex in the endosome dissociates at low pH followed by recycling of megalin to the cell‐surface while the LMW proteins are delivered to lysosomes for degradation. In Lowe syndrome/Dent‐2 disease (b), megalin trafficking to the cell surface is impaired. Owing to aberrant accumulation of actin at the endosomal membrane, megalin is retained in the endosome and missorted to the lysosome instead of being recycled to the brush border via recycling tubules. Source: https://onlinelibrary.wiley.com/doi/full/10.1111/tra.12160. Licensed under CC by 3.0.
Figure 3. Structure and function of the OCRL gene. Exome structure of OCRL gene incl. alternative splice site 18a (black boxes). Shaded boxes represent domains/binding sites of the OCRL‐1 protein. Dashed boxes refer to functions related to the different domains. In italics intracellular processes involving OCRL‐1. Source: https://link.springer.com/article/10.1007%2Fs00467‐016‐3343‐3. Licensed under CC by 4.0.
Figure 4. Distribution of mutations in Lowe syndrome and Dent‐2 disease. Frameshift and nonsense mutations are indicated using their cDNA numbering above the schematic representation of the cDNA, missense mutations and in‐frame deletions are presented below the cDNA and designated by their protein numbering. Mutations indicated in bold correspond to nonsense mutations, stars refer to intronic mutations leading to splicing defects. Horizontal bars indicate gross genomic deletions. Hichri et al. . Reproduced with permission of John Wiley and Sons.
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Further Reading

Lewis RA, Nussbaum RL and Brewer ED (2001) Lowe Syndrome. In: Pagon RA, Adam MP and Ardinger HH, et al. (eds) Gene Reviews® [Internet]. University of Washington, Seattle: Seattle (WA) (1993–2014) [Updated 2012 Feb 23].

Nussbaum RL and Suchy SF (2001) The oculocerebrorenal syndrome of Lowe. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease, 8th edn, pp 6257–6266. McGraw‐Hill: New York.

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Bökenkamp, Arend, and Ludwig, Michael(Jun 2019) Genetics of Lowe Oculocerebrorenal Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028661]