Oculocerebrorenal Syndrome of Lowe (Lowe syndrome) and Dent Disease - 2 via the OCRL Gene

The Oculocerebrorenal syndrome of Lowe (OCRL or Lowe syndrome) is a rare X-linked disorder, which is a characterized by a pleiotropic phenotype including congenital bilateral dense cataracts, infantile congenital muscular hypotonia, severe intellectual disability and Fanconi syndrome of the kidney proximal tubules (Lewis et al. 2012). Cataracts are always present at birth, whereas kidney dysfunction is not and may take several months to develop (Jänne et al. 1998). Other symptoms include infantile glaucoma (in ~50% of males), areflexia, seizures, maladaptive behavior, short stature, vitamin-D-resistant rickets, and scoliosis. All affected males have impaired vision (Lewis et al. 2012). Female carriers of Lowe syndrome show no clinical symptoms, however, ~95% do show characteristic lenticular opacities that was absent in all proven noncarriers (Röschinger et al. 2000; Jänne et al. 1998; Lewis et al. 2012).

Dent disease is an X-linked proximal renal tubule dysfunction disorder associated with low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Other symptoms include aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, impaired urinary acidification, and is occasionally complicated by rickets or osteomalacia. Males in their early childhood (< 10 yrs of age) show the disease phenotype, whereas female carriers may show a milder phenotype. The disease is advanced to end-stage renal disease (ESRD) in 30 to 80% of affected males around 3rd - 5th decades of life. To date, Dent’s disease has been reported in around 250 families (Devuyst and Thakker 2010; Lieske et al. 2012).

Lowe syndrome is an X-linked disorder caused by mutations in the OCRL gene. OCRL, which is located on chromosome Xq26.1. encodes phosphatidylinositol 4, 5-biphosphate 5-phosphatase (PIP2P) enzyme, which is localized to trans-Golgi network (TGN) and early endosomes. PIP2P is shown to be required for the clathrin-mediated trafficking between the TGN and early endosomes (Lowe 2005). An alternately spliced OCRL transcript is shown to be expressed in the brain (Sugimoto et al. 2014). PIP2P is highly homologous to inositol polyphosphate 5-phosphatase (INPP5B) and shares 45% sequence identity at the amino acid level and appear to have overlapping functions (Lowe 2005; Attree et al. 1992). Both INPP5B and PIP2P are also localized to the primary cilium and play compensatory roles in ciliogenesis (Luo et al. 2012). The majority of Lowe syndrome patients do not show detectable levels of OCRL mRNA transcripts or phosphatase activity 5 (Lin et al. 1997; Attree et al. 1992), suggesting that causative mutations in OCRL lead to loss-of-function (Satre et al. 1999; Lin et al. 1997; Lin et al. 1998). These studies indicate that Lowe syndrome may represent an inborn error of inositol phosphate metabolism (Lowe). Also, these results suggest that PIP2P assay is an accurate test for Lowe syndrome diagnosis. However, carrier testing is not feasible by this assay due to random X- inactivation in females (Lin et al. 1997). PIP2P is also a Rab effector protein and can bind to a variety of Rab proteins regulate targeted membrane trafficking between organelles (Hou et al. 2011). It has also been shown that the point mutations in OCRL that affects Rab protein binding lead to Lowe syndrome (Hagemann et al. 2012). Somatic and germline mosaicism have been reported in Lowe syndrome (Satre et al. 1999; Monnier et al. 2000). So far, over 150 and 30 causative sequence variations (missense, nonsense, splicing, small and gross insertions and deletions) in OCRL have been associated with Lowe syndrome and Dent disease - 2, respectively (Human Gene Mutation Database). Overall, ~70% of the missense mutations are located in exon 15, and 52% of all mutations are found within exons 11-15 (Satre et al. 1999).

CLCN5 is the main causative gene for Dent disease (accounts for ~ 60% of the cases), whereas mutations in OCRL accounts for only 15% of the cases. OCRL-associated Dent disease (Type 2) is always milder as compared to CLCN5 -associated Dent disease (Type 1) (Lieske et al. 1993).

OCRL molecular analysis in 9 probands and 26 relatives of Italian origin identified mutations in all nine patients (Addis et al. 2004). Another study indicates that ~ 90% of Lowe syndrome patients have OCRL mutations and new mutations occur in ~32% of the affected males (Sugimoto et al. 2014). Another analysis, which included samples from three probands and their family members (altogether 8 DNA samples), identified OCRL mutations in all probands, and their mothers were carriers of the respective mutations. These mutations were not found in 156 healthy controls (Ke et al. 2012).

This test provides full coverage of all coding exons of the OCRL gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).