Inositol 5-phosphatases: insights from the Lowe syndrome protein OCRL

Pirruccello, Michelle; Camilli, Pietro De

doi:10.1016/j.tibs.2012.01.002

Cited by 110 publications

(123 citation statements)

References 83 publications

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“…OCRL is an inositol polyphosphate 5-phosphatase that is implicated in Lowe syndrome and Dent disease (1,45,46). The recent discovery of its localization to cilia suggested its potential role in the pathophysiology of glaucoma in the TM of eyes (4,6,7).…”

Section: Discussionmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

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Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

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Section: Discussionmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

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“…10 Another possible diagnosis could be Dent's disease, a rare, X-linked, renal proximal tubulopathy, but without metabolic acidosis and ocular or brain involvement. 2,15,18 The management of our patient should include ophthalmic surgery for PCO, physical rehabilitation and supplements of bicarbonate, salt (potassium) and vitamin D. Unfortunately, we were unable to give vitamin D supplementation due to financial constraints. In addition, the surgery was cancelled due to the unstable serum electrolyte levels.…”

Section: Discussionmentioning

confidence: 99%

Management of Lowe syndrome: a case report

Prasetyo

Setiawan

Soemyarso

et al. 2015

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Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterized by anomalies affecting the eyes, nervous system and kidneys.1-3 The disorder was first recognized by Lowe et al. in 1952, and described as a unique syndrome with organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation. In 1954, renal Fanconi syndrome was recognized as being associated with Lowe syndrome and in 1965, a recessive X-linked pattern of inheritance was determined.2,4 Lowe syndrome is a very rare disease, with an estimated prevalence in the general population of 1 in 500,000. According to the Lowe Syndrome Association (LSA) in the USA, the estimated prevalence is between 1 and 10 affected males in 1,000,000 people, with 190 living in the year 2000. The Italian Association of Lowe Syndrome estimated that there were 34 Lowe syndrome patients (33 boys and one girl) living in Italy in the year 2005.2,4,5 It almost exclusively affects males.6 Physicians may not be familiar with Lowe syndrome due to its rarity.4

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“…This gene also plays an important role in the development of renal tubules, lens, and the brain. Although OCRL1 is widely expressed in different tissues, its expression may be defective during the development of the eye, kidney, and central neurological tissues, among others (Pirruccello and DeCamilli, 2012).…”

Section: Lowe Syndromementioning

confidence: 99%