Dataset Information

Identification and functional analysis of a novel oculocerebrorenal syndrome of Lowe (OCRL) gene variant in two pedigrees with varying phenotypes including isolated congenital cataract.

ABSTRACT: Purpose:To identify the genetic variation in two unrelated probands with congenital cataract and to perform functional analysis of the detected variants. Methods:Clinical examination and phenotyping, segregation, and functional analysis were performed for the two studied pedigrees. Results:A novel OCRL gene variant (c.1964A>T, p. (Asp655Val)) was identified. This variant causes defects in OCRL protein folding and mislocalization to the cytoplasm. In addition, the variant's location close to the Rab binding site is likely to be associated with membrane targeting abnormalities. Conclusions:The results highlight the importance of early genetic diagnosis in infants with congenital cataract and show that mutations in the OCRL gene can present as apparently isolated congenital cataract.

SUBMITTER: Shalaby AK

PROVIDER: S-EPMC6334980 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification and functional analysis of a novel oculocerebrorenal syndrome of Lowe (<i>OCRL</i>) gene variant in two pedigrees with varying phenotypes including isolated congenital cataract.

Shalaby Ahmed K AK Emery-Billcliff Peter P Baralle Diana D Dabir Tabib T Begum Shahiba S Waller Sarah S Tabernero Lydia L Lowe Martin M Self James J

Molecular vision 20181231

<h4>Purpose</h4>To identify the genetic variation in two unrelated probands with congenital cataract and to perform functional analysis of the detected variants.<h4>Methods</h4>Clinical examination and phenotyping, segregation, and functional analysis were performed for the two studied pedigrees.<h4>Results</h4>A novel <i>OCRL</i> gene variant (c.1964A>T, p. (Asp655Val)) was identified. This variant causes defects in OCRL protein folding and mislocalization to the cytoplasm. In addition, the var ...[more]

PMID: 30713423

Similar Datasets

Project description:Listeria monocytogenes is a bacterial pathogen that induces its own entry into a broad range of mammalian cells through interaction of the bacterial surface protein InlB with the cellular receptor Met, promoting an actin polymerization/depolymerization process that leads to pathogen engulfment. Phosphatidylinositol bisphosphate (PI[4,5]P(2)) and trisphosphate (PI[3,4,5]P(3)) are two major phosphoinositide species that function as molecular scaffolds, recruiting cellular effectors that regulate actin dynamics during L. monocytogenes infection. Because the phosphatidylinositol 5'-phosphatase OCRL dephosphorylates PI(4,5)P(2) and to a lesser extent PI(3,4,5)P(3), we investigated whether this phosphatase modulates cell invasion by L. monocytogenes. Inactivation of OCRL by small interfering RNA (siRNA) leads to an increase in the internalization levels of L. monocytogenes in HeLa cells. Interestingly, OCRL depletion does not increase but rather decreases the surface expression of the receptor Met, suggesting that OCRL controls bacterial internalization by modulating signaling cascades downstream of Met. Immuno-fluorescence microscopy reveals that endogenous and overexpressed OCRL are present at L. monocytogenes invasion foci; live-cell imaging additionally shows that actin depolymerization coincides with EGFP-OCRL-a accumulation around invading bacteria. Together, these observations suggest that OCRL promotes actin depolymerization during L. monocytogenes infection; in agreement with this hypothesis, OCRL depletion leads to an increase in actin, PI(4,5)P(2), and PI(3,4,5)P(3) levels at bacterial internalization foci. Furthermore, in cells knocked down for OCRL, transfection of enzymatically active EGFP-OCRL-a (but not of a phosphatase-dead enzyme) decreases the levels of intracellular L. monocytogenes and of actin associated with invading bacteria. These results demonstrate that through its phosphatase activity, OCRL restricts L. monocytogenes invasion by modulating actin dynamics at bacterial internalization sites.

Dataset Information

Identification and functional analysis of a novel oculocerebrorenal syndrome of Lowe (OCRL) gene variant in two pedigrees with varying phenotypes including isolated congenital cataract.

Publications

Identification and functional analysis of a novel oculocerebrorenal syndrome of Lowe (<i>OCRL</i>) gene variant in two pedigrees with varying phenotypes including isolated congenital cataract.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets