{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T03:27:18Z","timestamp":1771644438764,"version":"3.50.1"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,4]],"date-time":"2017-05-04T00:00:00Z","timestamp":1493856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,4]],"date-time":"2017-05-04T00:00:00Z","timestamp":1493856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in the <jats:italic>OCRL1<\/jats:italic> gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and neurological impairments. <jats:italic>OCRL1<\/jats:italic> encodes an inositol polyphosphate 5-phosphatase which preferentially dephosphorylates phosphatidylinositide 4,5 bisphosphate (PI(4,5)P<jats:sub>2<\/jats:sub>). We have identified two novel mutations in two unrelated Lowe syndrome patients with congenital glaucoma. Novel deletion mutations are detected at c.739-742delAAAG in Lowe patient 1 and c.1595-1631del in Lowe patient 2. End stage glaucoma in patient 2 resulted in the enucleation of the eye, which on histology demonstrated corneal keloid, fibrous infiltration of the angle, ectropion uvea, retinal gliosis, and retinal ganglion cell loss. We measured OCRL protein levels in patient keratinocytes and found that Lowe 1 patient cells had significantly reduced OCRL protein as compared to the control keratinocytes. Genotype-phenotype correlation of <jats:italic>OCRL1<\/jats:italic> mutations associated with congenital glaucoma revealed clustering of missense and deletion mutations in the 5-phosphatase domain and the RhoGAP-like domain. In conclusion, we report novel <jats:italic>OCRL1<\/jats:italic> mutations in Lowe syndrome patients and the corresponding histopathologic analysis of one patient\u2019s ocular pathology.<\/jats:p>","DOI":"10.1038\/s41598-017-01447-3","type":"journal-article","created":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T08:59:20Z","timestamp":1493283560000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis"],"prefix":"10.1038","volume":"7","author":[{"given":"Emilie","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8046-9372","authenticated-orcid":false,"given":"Na","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge A.","family":"Alvarado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathleen","family":"Walnuss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Neely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Spandau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alireza","family":"Ghaffarieh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,5,4]]},"reference":[{"key":"1447_CR1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1750-1172-1-16","volume":"1","author":"M Loi","year":"2006","unstructured":"Loi, M. Lowe syndrome. Orphanet J Rare Dis \n                           1, 16, doi:10.1186\/1750-1172-1-16 (2006).","journal-title":"Orphanet J Rare Dis"},{"key":"1447_CR2","unstructured":"Lewis, R. A., Nussbaum, R. L. & Brewer, E. D. In GeneReviews(R) (eds R. A., Pagon et al.) (University of Washington, Seattle, 1993)."},{"key":"1447_CR3","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1093\/hmg\/ddr608","volume":"21","author":"IB Ramirez","year":"2012","unstructured":"Ramirez, I. B. et al. Impaired neural development in a zebrafish model for Lowe syndrome. Hum Mol Genet \n                           21, 1744\u20131759, doi:10.1093\/hmg\/ddr608 (2012).","journal-title":"Hum Mol Genet"},{"key":"1447_CR4","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1007\/s00467-014-3013-2","volume":"30","author":"F Recker","year":"2015","unstructured":"Recker, F. et al. Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome. Pediatr Nephrol \n                           30, 931\u2013943, doi:10.1007\/s00467-014-3013-2 (2015).","journal-title":"Pediatr Nephrol"},{"key":"1447_CR5","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.2215\/CJN.00520108","volume":"3","author":"D Bockenhauer","year":"2008","unstructured":"Bockenhauer, D. et al. Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction. Clin J Am Soc Nephrol \n                           3, 1430\u20131436, doi:10.2215\/cjn.00520108 (2008).","journal-title":"Clin J Am Soc Nephrol"},{"key":"1447_CR6","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1093\/ndt\/gfg294","volume":"18","author":"L Tricot","year":"2003","unstructured":"Tricot, L. et al. End-stage renal failure in Lowe syndrome. Nephrol Dial Transplant \n                           18, 1923\u20131925 (2003).","journal-title":"Nephrol Dial Transplant"},{"key":"1447_CR7","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.bbrc.2008.02.067","volume":"369","author":"HJ McCrea","year":"2008","unstructured":"McCrea, H. J. et al. All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochem Biophys Res Commun \n                           369, 493\u2013499, doi:10.1016\/j.bbrc.2008.02.067 (2008).","journal-title":"Biochem Biophys Res Commun"},{"key":"1447_CR8","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1177\/0883073808321047","volume":"24","author":"A Yuksel","year":"2009","unstructured":"Yuksel, A., Karaca, E. & Albayram, M. S. Magnetic resonance imaging, magnetic resonance spectroscopy, and facial dysmorphism in a case of Lowe syndrome with novel OCRL1 gene mutation. J Child Neurol \n                           24, 93\u201396, doi:10.1177\/0883073808321047 (2009).","journal-title":"J Child Neurol"},{"key":"1447_CR9","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1002\/1098-1004(200008)16:2<157::AID-HUMU8>3.0.CO;2-9","volume":"16","author":"N Monnier","year":"2000","unstructured":"Monnier, N., Satre, V., Lerouge, E., Berthoin, F. & Lunardi, J. OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Human mutation \n                           16, 157\u2013165, doi:10.1002\/1098-1004(200008)16:2<157::aid-humu8>3.0.co;2-9 (2000).","journal-title":"Human mutation"},{"key":"1447_CR10","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1007\/s12519-011-0312-6","volume":"7","author":"VJ Lozanovski","year":"2011","unstructured":"Lozanovski, V. J., Ristoska-Bojkovska, N., Korneti, P., Gucev, Z. & Tasic, V. OCRL1 mutation in a boy with Dent disease, mild mental retardation, but without cataracts. World J Pediatr \n                           7, 280\u2013283, doi:10.1007\/s12519-011-0312-6 (2011).","journal-title":"World J Pediatr"},{"key":"1447_CR11","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s12098-014-1581-6","volume":"82","author":"T Liu","year":"2015","unstructured":"Liu, T., Yue, Z., Wang, H., Tong, H. & Sun, L. Novel mutation of OCRL1 in Lowe syndrome. Indian J Pediatr \n                           82, 89\u201392, doi:10.1007\/s12098-014-1581-6 (2015).","journal-title":"Indian J Pediatr"},{"key":"1447_CR12","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1053\/j.ajkd.2003.11.013","volume":"43","author":"L Schramm","year":"2004","unstructured":"Schramm, L. et al. Advanced renal insufficiency in a 34-year-old man with Lowe syndrome. Am J Kidney Dis \n                           43, 538\u2013543 (2004).","journal-title":"Am J Kidney Dis"},{"key":"1447_CR13","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1093\/hmg\/2.4.461","volume":"2","author":"AM Leahey","year":"1993","unstructured":"Leahey, A. M., Charnas, L. R. & Nussbaum, R. L. Nonsense mutations in the OCRL-1 gene in patients with the oculocerebrorenal syndrome of Lowe. Hum Mol Genet \n                           2, 461\u2013463 (1993).","journal-title":"Hum Mol Genet"},{"key":"1447_CR14","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1093\/hmg\/4.12.2245","volume":"4","author":"SF Suchy","year":"1995","unstructured":"Suchy, S. F., Olivos-Glander, I. M. & Nussabaum, R. L. Lowe syndrome, a deficiency of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi apparatus. Hum Mol Genet \n                           4, 2245\u20132250 (1995).","journal-title":"Hum Mol Genet"},{"key":"1447_CR15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s004390050329","volume":"99","author":"RL Nussbaum","year":"1997","unstructured":"Nussbaum, R. L., Orrison, B. M., Janne, P. A., Charnas, L. & Chinault, A. C. Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet \n                           99, 145\u2013150 (1997).","journal-title":"Hum Genet"},{"key":"1447_CR16","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1620\/tjem.232.163","volume":"232","author":"K Sugimoto","year":"2014","unstructured":"Sugimoto, K. et al. A novel OCRL1 mutation in a patient with the mild phenotype of Lowe syndrome. Tohoku J Exp Med \n                           232, 163\u2013166 (2014).","journal-title":"Tohoku J Exp Med"},{"key":"1447_CR17","doi-asserted-by":"publisher","first-page":"2846","DOI":"10.1016\/j.febslet.2012.07.037","volume":"586","author":"SE Conduit","year":"2012","unstructured":"Conduit, S. E., Dyson, J. M. & Mitchell, C. A. Inositol polyphosphate 5-phosphatases; new players in the regulation of cilia and ciliopathies. FEBS Lett \n                           586, 2846\u20132857, doi:10.1016\/j.febslet.2012.07.037 (2012).","journal-title":"FEBS Lett"},{"key":"1447_CR18","first-page":"817","volume":"57","author":"IM Olivos-Glander","year":"1995","unstructured":"Olivos-Glander, I. M., Janne, P. A. & Nussbaum, R. L. The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am J Hum Genet \n                           57, 817\u2013823 (1995).","journal-title":"Am J Hum Genet"},{"key":"1447_CR19","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1086\/302443","volume":"65","author":"V Satre","year":"1999","unstructured":"Satre, V. et al. Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene. Am J Hum Genet \n                           65, 68\u201376, doi:10.1086\/302443 (1999).","journal-title":"Am J Hum Genet"},{"key":"1447_CR20","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1038\/emboj.2009.155","volume":"28","author":"Y Mao","year":"2009","unstructured":"Mao, Y. et al. A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism. EMBO J \n                           28, 1831\u20131842, doi:10.1038\/emboj.2009.155 (2009).","journal-title":"EMBO J"},{"key":"1447_CR21","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1111\/j.1399-0004.1998.tb04284.x","volume":"54","author":"T Kubota","year":"1998","unstructured":"Kubota, T. et al. Identification of two novel mutations in the OCRL1 gene in Japanese families with Lowe syndrome. Clin Genet \n                           54, 199\u2013202 (1998).","journal-title":"Clin Genet"},{"key":"1447_CR22","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1002\/humu.9239","volume":"23","author":"M Addis","year":"2004","unstructured":"Addis, M., Loi, M., Lepiani, C., Cau, M. & Melis, M. A. OCRL mutation analysis in Italian patients with Lowe syndrome. Human mutation \n                           23, 524\u2013525, doi:10.1002\/humu.9239 (2004).","journal-title":"Human mutation"},{"key":"1447_CR23","first-page":"53","volume":"64","author":"L Chabaa","year":"2006","unstructured":"Chabaa, L. et al. [Oculo-cerebro-renal Lowe syndrome: clinical, biochemical and molecular studies in a Moroccan patient]. Ann Biol Clin (Paris) \n                           64, 53\u201359 (2006).","journal-title":"Ann Biol Clin (Paris)"},{"key":"1447_CR24","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1007\/s00439-010-0944-y","volume":"129","author":"M Draaken","year":"2011","unstructured":"Draaken, M. et al. Maternal de novo triple mosaicism for two single OCRL nucleotide substitutions (c.1736A\u2009>\u2009T, c.1736A\u2009>\u2009G) in a Lowe syndrome family. Hum Genet \n                           129, 513\u2013519, doi:10.1007\/s00439-010-0944-y (2011).","journal-title":"Hum Genet"},{"key":"1447_CR25","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1055\/s-0032-1321900","volume":"225","author":"SM Pasternack","year":"2013","unstructured":"Pasternack, S. M. et al. A premature termination mutation in a patient with Lowe syndrome without congenital cataracts: dropping the \u201cO\u201d in OCRL. Klin Padiatr \n                           225, 29\u201333, doi:10.1055\/s-0032-1321900 (2013).","journal-title":"Klin Padiatr"},{"key":"1447_CR26","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1002\/humu.21391","volume":"32","author":"H Hichri","year":"2011","unstructured":"Hichri, H. et al. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Human mutation \n                           32, 379\u2013388, doi:10.1002\/humu.21391 (2011).","journal-title":"Human mutation"},{"key":"1447_CR27","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1007\/s10157-008-0059-0","volume":"12","author":"SK Sethi","year":"2008","unstructured":"Sethi, S. K. et al. Mutations in OCRL1 gene in Indian children with Lowe syndrome. Clin Exp Nephrol \n                           12, 358\u2013362, doi:10.1007\/s10157-008-0059-0 (2008).","journal-title":"Clin Exp Nephrol"},{"key":"1447_CR28","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1034\/j.1399-0004.2000.580609.x","volume":"58","author":"J Peverall","year":"2000","unstructured":"Peverall, J., Edkins, E., Goldblatt, J. & Murch, A. Identification of a novel deletion of the entire OCRL1 gene detected by FISH analysis in a family with Lowe syndrome. Clin Genet \n                           58, 479\u2013482 (2000).","journal-title":"Clin Genet"},{"key":"1447_CR29","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1007\/s11255-012-0246-5","volume":"45","author":"R Peces","year":"2013","unstructured":"Peces, R. et al. A novel and de novo deletion in the OCRL1 gene associated with a severe form of Lowe syndrome. Int Urol Nephrol \n                           45, 1767\u20131771, doi:10.1007\/s11255-012-0246-5 (2013).","journal-title":"Int Urol Nephrol"},{"key":"1447_CR30","doi-asserted-by":"publisher","first-page":"140","DOI":"10.3345\/kjp.2014.57.3.140","volume":"57","author":"H-K Kim","year":"2014","unstructured":"Kim, H.-K. et al. Lowe syndrome: a single center\u2019s experience in Korea. Korean Journal of Pediatrics \n                           57, 140\u2013148, doi:10.3345\/kjp.2014.57.3.140 (2014).","journal-title":"Korean Journal of Pediatrics"},{"key":"1447_CR31","doi-asserted-by":"publisher","first-page":"12871","DOI":"10.1073\/pnas.1323292111","volume":"111","author":"N Luo","year":"2014","unstructured":"Luo, N. et al. Primary cilia signaling mediates intraocular pressure sensation. Proceedings of the National Academy of Sciences of the United States of America \n                           111, 12871\u201312876, doi:10.1073\/pnas.1323292111 (2014).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"1447_CR32","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera\u2013a visualization system for exploratory research and analysis. J Comput Chem \n                           25, 1605\u20131612, doi:10.1002\/jcc.20084 (2004).","journal-title":"J Comput Chem"},{"key":"1447_CR33","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.str.2014.01.013","volume":"22","author":"L Tresaugues","year":"2014","unstructured":"Tresaugues, L. et al. Structural basis for phosphoinositide substrate recognition, catalysis, and membrane interactions in human inositol polyphosphate 5-phosphatases. Structure \n                           22, 744\u2013755, doi:10.1016\/j.str.2014.01.013 (2014).","journal-title":"Structure"},{"key":"1447_CR34","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.devcel.2007.08.004","volume":"13","author":"KS Erdmann","year":"2007","unstructured":"Erdmann, K. S. et al. A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell \n                           13, 377\u2013390, doi:10.1016\/j.devcel.2007.08.004 (2007).","journal-title":"Dev Cell"},{"key":"1447_CR35","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/nsmb.2071","volume":"18","author":"M Pirruccello","year":"2011","unstructured":"Pirruccello, M., Swan, L. E., Folta-Stogniew, E. & De Camilli, P. Recognition of the F&H motif by the Lowe syndrome protein OCRL. Nat Struct Mol Biol \n                           18, 789\u2013795, doi:10.1038\/nsmb.2071 (2011).","journal-title":"Nat Struct Mol Biol"},{"key":"1447_CR36","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/humu.10212","volume":"21","author":"PD Stenson","year":"2003","unstructured":"Stenson, P. D. et al. Human Gene Mutation Database (HGMD): 2003 update. Human mutation \n                           21, 577\u2013581, doi:10.1002\/humu.10212 (2003).","journal-title":"Human mutation"},{"key":"1447_CR37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3928\/0191-3913-19810701-05","volume":"18","author":"J Ginsberg","year":"1981","unstructured":"Ginsberg, J., Bove, K. E. & Fogelson, M. H. Pathological features of the eye in the oculocerebrorenal (Lowe) syndrome. Journal of pediatric ophthalmology and strabismus \n                           18, 16\u201324 (1981).","journal-title":"Journal of pediatric ophthalmology and strabismus"},{"key":"1447_CR38","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1001\/archopht.1982.01030040775013","volume":"100","author":"GW Cibis","year":"1982","unstructured":"Cibis, G. W., Tripathi, R. C., Tripathi, B. J. & Harris, D. J. Corneal keloid in Lowe\u2019s syndrome. Archives of ophthalmology (Chicago, Ill.: 1960) \n                           100, 1795\u20131799 (1982).","journal-title":"Archives of ophthalmology (Chicago, Ill.: 1960)"},{"key":"1447_CR39","first-page":"132","volume":"100","author":"RC Tripathi","year":"1980","unstructured":"Tripathi, R. C., Cibis, G. W. & Tripathi, B. J. Lowe\u2019s syndrome. Transactions of the ophthalmological societies of the United Kingdom \n                           100, 132\u2013139 (1980).","journal-title":"Transactions of the ophthalmological societies of the United Kingdom"},{"key":"1447_CR40","doi-asserted-by":"publisher","first-page":"126","DOI":"10.3928\/0090-4481-19770101-08","volume":"6","author":"J Giangiacomo","year":"1977","unstructured":"Giangiacomo, J. Ocular manifestations of hereditary renal disorders. Pediatric annals \n                           6, 126\u2013129 (1977).","journal-title":"Pediatric annals"},{"key":"1447_CR41","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1097\/00004397-199303320-00017","volume":"33","author":"CW Lavin","year":"1993","unstructured":"Lavin, C. W. & McKeown, C. A. The oculocerebrorenal syndrome of Lowe. International ophthalmology clinics \n                           33, 179\u2013191 (1993).","journal-title":"International ophthalmology clinics"},{"key":"1447_CR42","first-page":"204","volume":"13","author":"BL Johnson","year":"1976","unstructured":"Johnson, B. L. & Hiles, D. A. Ocular pathology of Lowe\u2019s syndrome in a female infant. Journal of pediatric ophthalmology \n                           13, 204\u2013210 (1976).","journal-title":"Journal of pediatric ophthalmology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01447-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01447-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01447-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T04:03:07Z","timestamp":1671768187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01447-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,4]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["1447"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-01447-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,4]]},"assertion":[{"value":"8 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1442"}}