Two new missense mutations in the protein interaction ASH domain of OCRL1 identified in patients with Lowe syndrome

Abstract

The oculocerebrorenal syndrome of Lowe is a rare X-linked disease characterized by congenital cataracts, proximal renal tubulopathy, muscular hypotonia and mental impairment. This disease is caused by mutations in the OCRL gene encoding membrane bound inositol polyphosphate 5-phosphatase OCRL1. Here, we examined the OCRL gene of two Lowe syndrome patients and report two new missense mutations that affect the ASH domain involved in protein-protein interactions. Genomic DNA was extracted from peripheral blood of two non-related patients and their relatives. Exons and flanking intronic regions of OCRL were analyzed by direct sequencing. Several bioinformatics tools were used to assess the pathogenicity of the variants. The threedimensional structure of wild-type and mutant ASH domains was modeled using the online server SWISS-MODEL. Clinical features suggesting the diagnosis of Lowe syndrome were observed in both patients. Genetic analysis revealed two novel missense variants, c.1907T>A (p.V636E) and c.1979A>C (p.H660P) in exon 18 of the OCRL gene confirming the clinical diagnosis in both cases. Variant c.1907T>A (p.V636E) was inherited from the patient's mother, while variant c.1979A>C (p.H660P) seems to have originated de novo. Analysis with bioinformatics tools indicated that both variants are pathogenic. Both amino acid changes affect the structure of the OCRL1 ASH domain. In conclusion, the identification of two novel missense mutations located in the OCRL1 ASH domain may shed more light on the functional importance of this domain. We suggest that p.V636E and p.H660P cause Lowe syndrome by disrupting the interaction of OCRL1 with other proteins or by impairing protein stability.

An Update on the Oculocerebrorenal Syndrome of Lowe: A Review Article

“…Therefore, numerous studies have shown that OCRL-1 is preoccupied with various cellular activities having endocytic trafficking and skeletal dynamics of actin. These findings explain the different clinical symptoms of the disease (12,13).…”

“…The prenatal and postnatal distinctions are made by enzymatic and molecular analyses (2). Molecular studies should approve the clinical diagnosis of the OCRL1 gene; however, unfortunately, it is impossible to diagnose and evaluate all patients before birth (1,5,9,12,18). Before giving birth, it is necessary to check all suspected patients or family history (6,8,9).…”

“…The cause of LS is different types of OCRL genes on chromosome Xq25-26, encoding OCRL-1, an inositol 5-phosphatase inositol (2,8). This gene encodes a phosphatidylinositol bisphosphate-5-phosphatase, a site in the trans-Golgi complex active in actin polymerization (2,12). Some mutations in the OCRL gene stop the production of various enzymes caused by this gene.…”

“…Some mutations in the OCRL gene stop the production of various enzymes caused by this gene. Other mutations inhibit the enzyme's activity or prevent it from interacting with other proteins inside the cell (12)(13)(14)(15)(16).…”