This report describes Lowe oculocerebrorenal syndrome (OCRL), also called Lowe syndrome or oculocerebrorenal syndrome; OCRL exhibits X-linked recessive inheritance. The human gene implicated in this disease, also designated OCRL, encodes an inositol phosphatase that is involved in regulating membrane trafficking. There is a single orthologous gene in Drosophila, Dmel\Ocrl, for which RNAi constructs, an allele caused by insertional mutagenesis, and loss-of-function mutations caused by imprecise excision of the TE insertion have been generated. Dmel\Ocrl is also orthologous to a second related gene in human, INPP5B. The human OCRL gene is implicated in a second less severe disease, Dent disease 2 (MIM:300555), which is also associated with renal tubular defects.
The human OCRL gene has not been introduced into flies.
Animals homozygous for amorphic mutations of Dmel\Ocrl die during the larval or pupal stages. Larvae show a dramatic increase in the number of circulating hemocytes compared to controls and frequently display large melanotic masses in their posterior body cavity. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): H469R in the fly Ocrl gene [corresponds to H524R (H525R) in the human OCRL gene]. This variant form is unable to rescue the hemocyte phenotype.
Loss of Ocrl causes activation of multiple immune signaling pathways; results suggest that this activation arises from defective endosomal trafficking. Physical and genetic interactions of Dmel\Ocrl have been described; see below and in the Ocrl gene report.
[updated Mar. 2020 by FlyBase; FBrf0222196]
[LOWE OCULOCEREBRORENAL SYNDROME; OCRL](https://omim.org/entry/309000)
[OCRL INOSITOL POLYPHOSPHATE-5-PHOSPHATASE; OCRL](https://omim.org/entry/300535)
Dense congenital cataracts are found in all affected boys and infantile glaucoma in approximately 50%. All boys have impaired vision; corrected acuity is rarely better than 20/100. Generalized hypotonia is noted at birth and is of central (brain) origin. Motor milestones are delayed. Almost all affected males have some degree of intellectual disability. Affected males have varying degrees of proximal renal tubular dysfunction of the Fanconi type. Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease after age 10 to 20 years. [MedGen, Lowe syndrome; 2018.06.29]
Lowe syndrome is characterized by vision problems, including congenital cataracts, that are present at birth, kidney problems that usually develop in the first year of life, and brain abnormalities that are associated with intellectual disabilities. [NORD, Lowe syndrome, 2018.06.29]
Clinical features of Lowe syndrome are hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, amino aciduria, and reduced ammonia production by the kidney. [from MIM:309000; 2018.06.19]
Lowe oculocerebrorenal syndrome (OCRL) is caused by mutation in the OCRL gene, which encodes phosphatidylinositol 4,5-bisphosphate-5-phosphatase. Lowe syndrome exhibits X-linked recessive inheritance. [from MIM:309000 and MIM:300535; 2018.06.19]
OCRL gene encodes an inositol polyphosphate 5-phosphatase, which is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane.
The OCRL gene encodes a phosphatidylinositol 4,5-bisphosphate-5-phosphatase localized to the trans-Golgi network that is involved in actin polymerization (Suchy and Nussbaum, 2002; pubmed:12428211). [from MIM:300535; 2018.06.19]
Many to one: 2 human to 1 Drosophila; the other human gene is INPP5B.
High-scoring ortholog of human OCRL and INPP5B (1 Drosophila to 2 human). Dmel\Ocrl shares 29-30% identity and 45-49% similarity with the human genes.
