A Common Founder Mutation of<i>CERKL</i>Underlies Autosomal Recessive Retinal Degeneration with Early Macular Involvement among Yemenite Jews

Auslender, Noa; Sharon, Dror; Abbasi, Anan H; Garzozi, Hanna J.; Banin, Eyal; Ben-Yosef, Tamar

doi:10.1167/iovs.07-0736

Cited by 58 publications

(51 citation statements)

References 12 publications

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“…Conversely, CERKL mutants which cannot activate TRX 2 will leave the uprising ROS untreated [15], which may induce photoreceptor apoptosis gradually by oxidative damage [4], the ROS induced ceramide [68], endoplasmic reticulum stress (ER stress) [4] and even inflammation [69]. Consistent with this, patients with CERKL mutation show prominently maculopathy [11,18], a pathological state in the macula strongly associates with oxidative stress [70] and inflammation [69]. This is also evidenced in animal models, strong signs of oxidative damage were observed in their retinas once CERKL was knockdown [15] or knockout [19].…”

Section: Discussionmentioning

confidence: 75%

“…Mutations of the ceramide kinase like (CERKL) gene, including premature terminations [9,10], splice sites [11] and point mutations [12], are responsible for autosomal recessive RP (RP26). Although CERKL is homologous to ceramide kinase (CERK), it does not phosphorylate ceramide [13].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, CERKL is an mRNA binding protein and localizes in a cytoplasmic RNA-protein complex called stress granules (SGs), which increases in response to stress conditions [16]. CERKL is critical to photoreceptor survival but not development [17], its deficiency leads to retinal degeneration as a result of oxidative damage in both human [11,18] and animal models [15,17,19]. Although it is pivotal for photoreceptor survival, the regulatory mechanism of CERKL in response to stress remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation

Chen

Liu

et al. 2015

Cellular Signalling

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation

Chen

Liu

et al. 2015

Cellular Signalling

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“…The fi nding that mutations in a novel Cer kinase (CerK) homologous gene, the CerK-like protein (CerKL) cause an autosomal recessive form of retinitis pigmentosa (RP) ( 147,148 ) provided the fi rst direct link between sphingolipid metabolism and human retinal degeneration. Early macular degeneration and cone and rod involvement are common outcomes of the two CERKL mutations identifi ed.…”

Section: Ceramide In the Retinamentioning

confidence: 99%

Regulating survival and development in the retina: key roles for simple sphingolipids

Rotstein

Miranda

Abrahan

et al. 2010

Journal of Lipid Research

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tions as structural membrane components and energetic fuels. However, the fi ndings of the previous half century have extended these roles, shedding light on their indisputable relevance as signaling molecules controlling key aspects of cellular life and development. The identifi cation of diacylglycerol and inositol 1,4,5 triphosphate ( 1 ) as second messengers seemed at the time a peculiarity of these lipids. The subsequent fi ndings of the roles of arachidonic acid metabolites ( 2 ), platelet activating factor ( 3 ), and other minor inositol lipids ( 4 ) in cell signaling began to establish that being intracellular messengers was not an oddity but a habitual task for lipids in cells. The family of lipid signaling molecules largely expanded in the last two decades, when several sphingolipids were successively shown to regulate a multiplicity of cell functions. Sphingosine (Sph) was the fi rst sphingolipid to be established as a bioactive lipid, involved in the regulation of protein kinase (PK)C activity ( 5 ). Ceramide (Cer) and sphingosine-1-phosphate (S1P) were next shown to signal a myriad of cell functions and the number of sphingolipid molecules with bioactive properties has gone on enlarging in recent years ( 6, 7 ).Though a vast literature exists on the functions of sphingolipids in several tissues, less is known concerning its roles in the eye, and in the retina in particular. Accumulation of sphingolipids originated in defects in the lysosomal Abstract Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces infl ammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors. When asked about the roles of cellular lipids, the fi rst thought usually coming to our minds re...

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“…In humans, mutations in Ceramide kinase like gene (CERKL) are associated with RP26 (Auslender et al, 2007;Tuson et al, 2004). Since CERKL is involved in ceramide metabolism, this suggests a link between ceramide and human retinal apoptosis.…”

Section: Sphingolipids and Cell Deathmentioning

confidence: 99%

Pharmacological approaches to retinitis pigmentosa: A laboratory perspective

Guadagni

Novelli

Piano

et al. 2015

Progress in Retinal and Eye Research

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A Common Founder Mutation ofCERKLUnderlies Autosomal Recessive Retinal Degeneration with Early Macular Involvement among Yemenite Jews

Cited by 58 publications

References 12 publications

pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation

pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation

Regulating survival and development in the retina: key roles for simple sphingolipids

Pharmacological approaches to retinitis pigmentosa: A laboratory perspective

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