Mutations in STRA6 Cause a Broad Spectrum of Malformations Including Anophthalmia, Congenital Heart Defects, Diaphragmatic Hernia, Alveolar Capillary Dysplasia, Lung Hypoplasia, and Mental Retardation

Pasutto, Francesca; Sticht, Heinrich; Hammersen, G.; Gillessen‐Kaesbach, Gabriele; FitzPatrick, David R.; Nürnberg, Gudrun; Brasch, Frank; Schirmer-Zimmermann, Heidemarie; Tolmie, John; Chitayat, David; Houge, Gunnar; Fernández-Martínez, Lorena T.; Keating, Sarah; Mortier, Geert; Hennekam, Raoul C. M.; Wense, A. von der; Slavotinek, Anne; Meinecke, Peter; Bitoun, Pierre; Becker, Christian; Nürnberg, Peter; Reis, André; Rauch, Anita

doi:10.1086/512203

Cited by 312 publications

(375 citation statements)

References 35 publications

(38 reference statements)

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“…This was confirmed by the fact that Stra6 mutations observed in humans are responsible for familial syndromes likely to be related to the role of vitamin A in embryonic development, 21 which include severe malformations such as anophtalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary displasia, lung hypoplasia and mental retardation. 23 Consistent with this, a Stra6 knockout mouse model showed several ocular defects similar to those described in humans. 24 Moreover, after binding to holo-RBP, Stra6 is phosphorylated when retinol is internalized and transferred to CRBP-I.…”

supporting

confidence: 64%

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

et al. 2013

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Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.

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supporting

confidence: 64%

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

et al. 2013

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“…In addition, at some tissues, holo-RBP4 is recognised by a plasma membrane receptor termed stimulated by retinoic acid 6 (STRA6), that transports retinol from the binding protein into cells (10) . In the adult, STRA6 is expressed in blood-organ barriers, retinal pigment epithelium cells of the eye, brain, spleen, kidney, testis, female genital tract and adipose tissue but not in the liver or in the colon (11,12) . Surprisingly, characterization of STRA6-null mice showed that the receptor is not necessary for maintaining proper retinoid content of tissues other than the eye, and that its ablation does not disrupt physiological functions that critically depend on vitamin A either during embryonic development or in the adult (13)(14)(15) .…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

“…STRA6 recruits STAT through an amino acid sequence in the receptor's intracellular domain that contains a consensus phosphotyrosine motif (12) . Holo-RBP4 thus functions as a classical cytokine to activate a STRA6/JAK2/ STAT3/5 pathway.…”

Section: Stra6 a Cytokine Signalling Receptor Activated By Holo-retimentioning

confidence: 99%

Vitamin A in regulation of insulin responsiveness: mini review

Noy

2016

Proc. Nutr. Soc.

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Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples 'sensing' of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.

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“…The advantage of the second approach is that it can provide the biochemical basis for the human genetics of STRA6. Recent human genetic studies found that mutations in STRA6 are associated with severe pathological phenotypes such as mental retardation, anophthalmia, congenital heart defects, lung hyperplasia, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation (28,29). In this study, we identified the functional defects in these naturally occurring human STRA6 mutants and polymorphisms.…”

Section: Plasma Retinol-binding Protein (Rbp)mentioning

confidence: 99%

An Essential Ligand-binding Domain in the Membrane Receptor for Retinol-binding Protein Revealed by Large-scale Mutagenesis and a Human Polymorphism

Kawaguchi

Wiita

et al. 2008

Journal of Biological Chemistry

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Plasma retinol-binding protein (RBP), the principal carrier of vitamin A in the blood, delivers vitamin A from liver, the site of storage, to distant organs that need vitamin A, such as the eye, brain, placenta, and testis. STRA6 is a high-affinity membrane receptor for RBP and mediates vitamin A uptake in these target organs. STRA6 is a 74-kDa multi-transmembrane domain protein that represents a new class of membrane transport protein.In this study, we used an unbiased strategy by analyzing >900 random mutants of STRA6 to study its structure and function, and we identified an essential RBP-binding domain in STRA6. Mutations in any of the three essential residues in this domain can almost completely abolish binding of STRA6 to RBP and its vitamin A uptake activity from holo-RBP without affecting its cell surface expression. We have also functionally characterized the mutations in human STRA6 that cause severe birth defects as well as several human polymorphisms. All STRA6 mutants associated with severe birth defects have largely abolished vitamin A uptake activity, consistent with the severe clinical phenotypes. In addition, we have identified a human polymorphism that significantly reduces the vitamin A uptake activity of STRA6. Interestingly, the residue affected by this polymorphism is located in the RBP-binding domain we identified, and the polymorphism causes decreased vitamin A uptake by reducing RBP binding. This study identifies an essential functional domain in STRA6 and a human polymorphism in this domain that leads to reduced vitamin A uptake activity. Plasma retinol-binding protein (RBP)2 is the principal carrier of vitamin A in the blood (1-4). It was first proposed in the 1970s that there exists a cell surface receptor that mediates vitamin A uptake from RBP on the retinal pigment epithelium and small intestine cells (5-10). During the past 3 decades, there has been mounting evidence for the existence of RBP receptors on diverse types of tissues, including the placenta (11-13), choroid plexus (12, 14), Sertoli cells and peritubular cells of the testis (12,(15)(16)(17)(18), macrophages (19), and skin (12,20). There are also indirect pieces of evidence for the existence of an RBP receptor. For example, in an unbiased search for a serum factor that stimulates the growth of B cells, it was found that the vitamin A-RBP complex (holo-RBP) is this factor (21). Using an unbiased strategy combining photo-cross-linking, high-affinity purification, and mass spectrometry, the RBP receptor was identified as STRA6, a multi-transmembrane protein of previously unknown function (22). STRA6 binds to RBP with high affinity and specificity and facilitates the transport of vitamin A into the cell. STRA6 was originally identified as a retinoic acid-stimulated gene in cancer cell lines (23, 24).STRA6 has not been systematically characterized at the structural and functional level and is not homologous to any protein with known function. In this study, we used two complementary approaches to study the structure and functi...

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Mutations in STRA6 Cause a Broad Spectrum of Malformations Including Anophthalmia, Congenital Heart Defects, Diaphragmatic Hernia, Alveolar Capillary Dysplasia, Lung Hypoplasia, and Mental Retardation

Cited by 312 publications

References 35 publications

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

Vitamin A in regulation of insulin responsiveness: mini review

An Essential Ligand-binding Domain in the Membrane Receptor for Retinol-binding Protein Revealed by Large-scale Mutagenesis and a Human Polymorphism

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