Role of Ocrl1 in Primary Cilia Assembly

Madhivanan, Kayalvizhi; Ramadesikan, Swetha; Aguilar, R. Claudio

doi:10.1016/bs.ircmb.2015.02.003

Cited by 15 publications

(18 citation statements)

References 47 publications

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“…In vitro studies using human and animal cells have shown that the 5-phosphatase and RhoGAP domains are involved with the localization of ocrl1 to the primary cilium 12,34 and its ability to modulate the length of the primary cilium. 11 INPP5B has also been shown to be a positive modulator of ciliogenesis and ciliary length.…”

Section: Discussionmentioning

confidence: 99%

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Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

et al. 2016

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OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, de novo DD2-causing 462 bp deletion disrupting exon 3 of OCRL1 and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10−6) damaging missense mutation in INPP5B (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein’s critical PH domain. In silico analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human OCRL paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3 metabolism in this mechanism.

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Section: Discussionmentioning

confidence: 99%

“…10–12 This protein has been linked to multiple key intracellular functions including vesicle trafficking, cytoskeleton stability due to α-actin distribution and ciliogenesis, in addition to intrinsic Rho GTPase binding. 12 …”

Section: Introductionmentioning

confidence: 99%

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

et al. 2016

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“…One of the main routes of PIP2 synthesis is thought to be by PI5K and PI4K kinasedependent phosphorylation of PI(4)P and PI(5)P, respectively (Schramp et al, 2015). PI(4)P was shown to be highly enriched in PC of several cell types (Chávez et al, 2015;Garcia-Gonzalo et al, 2015) under the tight control of INPP5E which seems not to use PI5P as a substrate (Kisseleva et al, 2000;Madhivanan et al, 2015;Schramp et al, 2015;Conduit et al, 2017). A novel specific for PI4P probe, P4M-SidM tagged with mCherry showed surprisingly low abundance in the olfactory cilia of the control WT mice (Fig.…”

Section: Deficiency Of Inpp5e Also Affects Other Phospholipids In Osnsmentioning

confidence: 99%

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ukhanov

Uytingco

Green

et al. 2018

Preprint

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Ciliopathies manifested in part by a dysfunction of several phosphoinositide 5'phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3 in knobs.Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation.However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level.These findings implicate phosphoinositide-dependent regulation of active Ca 2+ extrusion in OSNs whereby controlling the rate of sensory adaptation. Significance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild type INPP5E to the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.

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“…Por tanto, la presencia de esta mutación compromete la actividad enzimática y la estabilidad de la proteína (Li, et al, 2016). Lo que explicaría, la acumulación de fosfatidilinositol 4,5-bifosfato en las células y defectos en la distribución de alfa-actina, F-actina y la ciligenesis principalmente en la alteración de la formación de los cilios primarios (CP) (Madhivanan, et al, 2015); que son extensiones dinámicas de la membrana que poseen características muy específicas y su formación al igual que su mantenimiento dependen del tráfico vesicular (Madhivanan & Aguilar, 2014). Estas estructuras están presentes de manera semipermanente en muchas células diferenciadas, incluyendo las células epiteliales del túbulo renal, fibroblastos y neuronas, que hacen parte de algunos de los tejidos comprometidos en estos síndromes.…”

Section: Glaucomaunclassified

“…En su estructura OCRL1 posee cuatro dominios: PH (dominio con homología a Pleckstrina), RhoGAP (Proteina activadora Rho GTPasa), 5-fosfatasa y ASH (ASPM-SPD2-Hidina) (Madhivanan, Ramadesikan & Aguilar, 2015), dos cajas de clatrina (Pirruccello & De Camilli, 2012), que están implicadas en la polimerización de actina, el transporte de proteínas y la señalización celular (Krauß & Haucke, 2007). Se han relacionado dos fenotipos distintos a nivel celular para este síndrome implicados en la remodelación de la membrana y los cilios primarios, los cuales se hayan vinculados a defectos en el dominio RhoGAP (Conduit, Dyson, Mitchell, 2012).…”

Section: Introductionunclassified

Red de interacción proteína-proteína de fosfatidilinositol 4,5-bifosfato 5-fosfatasa relacionada con el síndrome de Lowe

Baldiris-Avila

Acosta

Arzuza-Romero

et al. 2016

Rev. Acad. Colomb. Cienc. Ex. Fis. Nat.

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ResumenEl síndrome de Lowe (SL) es una enfermedad transmitida por herencia ligada al sexo, que afecta mayoritariamente a los hombres y muy ocasionalmente a las mujeres. El SL consiste en mutaciones en el gen OCRL1 que afectan el metabolismo del inositol fosfato, produciendo afecciones significativas de los ojos, el sistema nervioso y los riñones. En este estudio se construyó una red de interacción proteína-proteína para la enzima fosfatidilinositol 4,5-bifosfato 5-fosfatasa, en el software Cytoscape versión 3.3.0, a partir de información suministrada por las bases de datos KEGG, PubMed, BioGRID, STRING y Uniprot, donde se extrajeron 26 proteínas relacionadas con OCRL. Con base en un análisis funcional y topológico, se obtuvo que las categorías ontológicas (GO) de mayor significancia están relacionadas con el transporte mediado por vesículas y la transducción de señales medidas por pequeñas GTPasas. Por otro lado, los parámetros topológicos de la red construida fueron, coeficiente de transitividad: 0,033, diámetro: 5,0 centralización: 0,55.© 2016. Acad. Colomb. Cienc. Ex. Fis. Nat. Palabras Clave: Síndrome de Lowe; Cytoscape 3.3.0; OCRL; Bioinformática; PPIs. Network of protein-protein interaction of phosphatidylinositol 4, 5-bisphosphate 5-phosphatase, related with Lowe syndrome AbstractLowe syndrome is a disease transmitted by sex-linked inheritance. That mainly affects males, and very occasionally women. It consists of a mutation in the gene OCRL1 that affects inositol phosphate metabolism, producing significant problems on the eye, nervous system and kidneys. A network of protein-protein interaction for the enzyme phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Cytoscape software version 3.3.0 was build, from the information provided by the KEGG database, PubMed, BioGrid, STRING, Uniprot data, 26 proteins were extracted related with OCRL. Based on a functional and topological analysis, was obtained ontological categories (GO) of greater significance are related mediated transport vesicles and signal transduction steps by small GTPases. On the other hand, topological parameters of the network were built, transitivity coefficient: 0.033, diameter: 5,0 centralization: 0.55. © 2016. Acad. Colomb. Cienc. Ex. Fis. Nat. IntroducciónEl síndrome de Lowe o distrofia óculo-cerebro-renal es una enfermedad hereditaria transmitida por herencia recesiva ligada al cromosoma X, por lo que afecta en la mayoría de los casos a los hombres; las anomalías genéticas relacionadas con este síndrome se producen por deleciones, translocaciones y mutaciones stop, con una fracción más pequeña que ocurre como splicing y mutaciones sin sentido (Pirruccello & De Camilli, 2012). Ocasionalmente se han reportado algunos casos en que este síndrome se expresa en las mujeres, que por lo general, se explica por hipótesis de Lyon o por heterogeneidad genética. Sin embargo, estudios recientes han demostrado que la causa más probable de la aparición en mujeres es una translocación del segmento del cromosoma X que contiene el gen, a un aut...

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Role of Ocrl1 in Primary Cilia Assembly

Cited by 15 publications

References 47 publications

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Red de interacción proteína-proteína de fosfatidilinositol 4,5-bifosfato 5-fosfatasa relacionada con el síndrome de Lowe

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