{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:47:29Z","timestamp":1785836849257,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Prompted by a fetus with a homozygous PPP1R13L pathogenic variant and persistent open eyelids on sonography, suggesting fusion failure, this study marks the first prenatal human description linking PPP1R13L to eyelid closure, mirroring waved with open eyelids 2(woe2) and waved 3 (wa3) mouse models. Eyelid morphogenesis involves complex epidermal\u2013dermal interactions. We reviewed the literature to understand embryonic\/fetal development and identify molecular pathways crucial for proper eyelid morphology. Known signaling pathways in eyelid closure and reopening include NF-\u03baB, p53, Wnt, TGF-\u03b2, BMP4, MAPK, SMAD, ECM\u2013receptor interaction, and integrin signaling. Open-eye phenotypes are associated with pathogenic variants affecting the Wnt\/\u03b2-catenin pathway, p63, and the TGF\u03b2 family. Notably, SMAD molecules are common to all these pathways. Eyelid closure seems regulated by SMAD protein activation in the supraorbital epithelium and underlying mesenchyme, promoting cell proliferation and adhesion. Physiological SMAD1 downregulation is crucial for eyelid reopening. Given SMAD signaling\u2019s importance in development, its disruption likely impacts eyelid closure or reopening.<\/jats:p>","DOI":"10.3390\/ijms27156991","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:15:22Z","timestamp":1785834922000},"page":"6991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Failure to Fuse Shut Eyelids, a Novel Unique Sign in Affected Fetus with Homozygous PPP1R13L Pathogenic Variant\u2014A Case Report and Review of the Literature"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7358-9712","authenticated-orcid":false,"given":"Zaher","family":"Shalata","sequence":"first","affiliation":[{"name":"S.B.A Rihana Medical Center, Sakhnin 30810, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hila","family":"Mintz","sequence":"additional","affiliation":[{"name":"The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa 31048, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Haddad","sequence":"additional","affiliation":[{"name":"The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa 31048, Israel"},{"name":"Obstetrics-Gynecology Ultrasound Unit, Bnai-Zion Medical Center, Haifa 31048, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled","family":"Osman","sequence":"additional","affiliation":[{"name":"The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa 31048, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Mahroum","sequence":"additional","affiliation":[{"name":"The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa 31048, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yarin","family":"Hadid","sequence":"additional","affiliation":[{"name":"The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa 31048, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5209-2072","authenticated-orcid":false,"given":"Adel","family":"Shalata","sequence":"additional","affiliation":[{"name":"S.B.A Rihana Medical Center, Sakhnin 30810, Israel"},{"name":"The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa 31048, Israel"},{"name":"The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa 32000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2414","DOI":"10.1002\/bdr2.2414","article-title":"Prevalence of Congenital Ocular Anomalies in 15 Countries of Europe: Results From the Medikeye Study","volume":"116","author":"Dubucs","year":"2024","journal-title":"Birth Defects Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/bdr2.1413","article-title":"Population-Based Birth Defects Data in the United States, 2011\u20132015: A Focus on Eye and Ear Defects","volume":"110","author":"Stallings","year":"2018","journal-title":"Birth Defects Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/j.ophtha.2009.05.018","article-title":"A Surgical Strategy for the Correction of Fraser Syndrome Cryptophthalmos","volume":"116","author":"Saleh","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1242\/dev.01892","article-title":"A Dual Role of FGF10 in Proliferation and Coordinated Migration of Epithelial Leading Edge Cells during Mouse Eyelid Development","volume":"132","author":"Tao","year":"2005","journal-title":"Development"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R269","DOI":"10.1093\/hmg\/ddi262","article-title":"The Genetics of Fraser Syndrome and the Blebs Mouse Mutants","volume":"14","author":"Smyth","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.matbio.2007.05.008","article-title":"Basement Membrane Localization of Frem3 Is Independent of the Fras1\/Frem1\/Frem2 Protein Complex within the Sublamina Densa","volume":"26","author":"Petrou","year":"2007","journal-title":"Matrix Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.yexcr.2006.12.008","article-title":"Overlapping and Divergent Localization of Frem1 and Fras1 and Its Functional Implications during Mouse Embryonic Development","volume":"313","author":"Petrou","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S1542-0124(12)70102-7","article-title":"Signaling Pathways in Morphogenesis of Cornea and Eyelid","volume":"6","author":"Kao","year":"2008","journal-title":"Ocul. Surf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jtos.2012.07.005","article-title":"Wakayama Symposium: Epithelial-Mesenchymal Interactions in Eyelid Development","volume":"10","author":"Ohuchi","year":"2012","journal-title":"Ocul. Surf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ydbio.2004.09.022","article-title":"Excess Biglycan Causes Eyelid Malformation by Perturbing Muscle Development and TGF-Alpha Signaling","volume":"277","author":"Hayashi","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_11","first-page":"33","article-title":"The Development of the Eyelids. Part I. External Features","volume":"130","author":"Pearson","year":"1980","journal-title":"J. Anat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/eye.1988.25","article-title":"A Reappraisal of the Development of the Eyelids","volume":"2","author":"Sevel","year":"1988","journal-title":"Eye"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1097\/IOP.0000000000000702","article-title":"Embryologic and Fetal Development of the Human Eyelid","volume":"32","author":"Tawfik","year":"2016","journal-title":"Ophthal. Plast. Reconstr. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1002\/ar.21366","article-title":"Timetable for Upper Eyelid Development in Staged Human Embryos and Fetuses","volume":"294","author":"Byun","year":"2011","journal-title":"Anat. Rec."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Willett, S.M., Maenner, S.K., and Mayo, J.P. (2023). The Perceptual Consequences and Neurophysiology of Eye Blinks. Front. Syst. Neurosci., 17.","DOI":"10.3389\/fnsys.2023.1242654"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/jcu.10173","article-title":"Eyelid Movements in Normal Human Fetuses","volume":"31","author":"Petrikovsky","year":"2003","journal-title":"J. Clin. Ultrasound"},{"key":"ref_17","first-page":"275","article-title":"Eye Blink in Newborn and Preschool-Age Children","volume":"86","author":"Lavezzo","year":"2008","journal-title":"Acta Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"319","DOI":"10.15252\/emmm.201606523","article-title":"Sequence Variation in PPP1R13L Results in a Novel Form of Cardio-Cutaneous Syndrome","volume":"9","author":"Barsheshet","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.gheart.2017.01.003","article-title":"The 22q11.2 Deletion Syndrome in Congenital Heart Defects: Prevalence of Microdeletion Syndrome in Cameroon","volume":"12","author":"Wonkam","year":"2017","journal-title":"Glob. Heart"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1177\/1055665620954090","article-title":"Dental and Craniofacial Characteristics in Patients With 14Q22.1\u2013Q22.2 Deletion: A Case Series","volume":"58","author":"Roelandt","year":"2021","journal-title":"Cleft Palate Craniofacial J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ejmg.2013.01.005","article-title":"3q26.33\u20133q27.2 Microdeletion: A New Microdeletion Syndrome?","volume":"56","author":"Mandrile","year":"2013","journal-title":"Eur. J. Med. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s12041-021-01261-x","article-title":"Expanding the Phenotype Associated with Interstitial 6p25.1p24.3 Microdeletion: A New Case and Review of the Literature","volume":"100","author":"Tassano","year":"2021","journal-title":"J. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1002\/ajmg.a.37840","article-title":"V 8q21.11 Microdeletion in Two Patients with Syndromic Peters Anomaly","volume":"170","author":"Happ","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ajoc.2018.11.001","article-title":"V Exposure, Entropion, and Bilateral Corneal Ulceration in a Newborn as a Manifestation of Chromosome 22 Q11.2 Duplication Syndrome","volume":"13","author":"Moein","year":"2019","journal-title":"Am. J. Ophthalmol. Case Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17050","DOI":"10.1038\/hgv.2017.50","article-title":"The Smallest de Novo 20q11.2 Microdeletion Causing Intellectual Disability and Dysmorphic Features","volume":"4","author":"Hanafusa","year":"2017","journal-title":"Hum. Genome Var."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1002\/ajmg.a.32440","article-title":"Molecular Study of 33 Families with Fraser Syndrome New Data and Mutation Review","volume":"146A","author":"Maiburg","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.biocel.2010.12.016","article-title":"The Role of Fras1\/Frem Proteins in the Structure and Function of Basement Membrane","volume":"43","author":"Pavlakis","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kalayinia, S., Mahdavi, M., Houshmand, G., Hesami, M., Pourirahim, M., and Maleki, M. (2022). Novel Homozygous Stop-Gain Pathogenic Variant of PPP1R13L Gene Leads to Arrhythmogenic Cardiomyopathy. BMC Cardiovasc. Disord., 22.","DOI":"10.1186\/s12872-022-02802-7"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Toonen, J., Liang, L., and Sidjanin, D.J. (2012). Waved with Open Eyelids 2 (Woe2) Is a Novel Spontaneous Mouse Mutation in the Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 13 like (Ppp1r13l) Gene. BMC Genet., 13.","DOI":"10.1186\/1471-2156-13-76"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1093\/hmg\/ddi063","article-title":"A Mutation in NFkB Interacting Protein 1 Results in Cardiomyopathy and Abnormal Skin Development in Wa3 Mice","volume":"14","author":"Herron","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.jtos.2023.07.007","article-title":"Wnt\/\u03b2-Catenin Signaling Controls Mouse Eyelid Growth by Mediating Epithelial-Mesenchymal Interactions","volume":"29","author":"Zhu","year":"2023","journal-title":"Ocul. Surf."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0092-8674(93)90228-I","article-title":"TGF Alpha Deficiency Results in Hair Follicle and Eye Abnormalities in Targeted and Waved-1 Mice","volume":"73","author":"Luetteke","year":"1993","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0092-8674(93)90227-H","article-title":"Mice with a Null Mutation of the TGF Alpha Gene Have Abnormal Skin Architecture, Wavy Hair, and Curly Whiskers and Often Develop Corneal Inflammation","volume":"73","author":"Mann","year":"1993","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S1534-5807(03)00161-8","article-title":"C-Jun Regulates Eyelid Closure and Skin Tumor Development through EGFR Signaling","volume":"4","author":"Zenz","year":"2003","journal-title":"Dev. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.str.2007.11.012","article-title":"Biochemical and Structural Studies of ASPP Proteins Reveal Differential Binding to P53, P63, and P73","volume":"16","author":"Robinson","year":"2008","journal-title":"Structure"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0925-4773(98)00145-2","article-title":"Role of Integrins in Mouse Eyelid Development: Studies in Normal Embryos and Embryos in Which There Is a Failure of Eyelid Fusion","volume":"78","author":"Carroll","year":"1998","journal-title":"Mech. Dev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.exer.2017.04.006","article-title":"Role of EGF Receptor Signaling on Morphogenesis of Eyelid and Meibomian Glands","volume":"163","author":"Dong","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1101\/gad.8.4.414","article-title":"Activin\/Inhibin Beta B Subunit Gene Disruption Leads to Defects in Eyelid Development and Female Reproduction","volume":"8","author":"Vassalli","year":"1994","journal-title":"Genes Dev."},{"key":"ref_39","first-page":"793","article-title":"Disruption of Eyelid and Cornea Morphogenesis by Epithelial \u03b2-Catenin Gain-of-Function","volume":"21","author":"Mizoguchi","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.bbrc.2010.08.065","article-title":"Inactivation of Smad4 Leads to Impaired Ocular Development and Cataract Formation","volume":"400","author":"Liu","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"252","DOI":"10.3109\/13816810.2015.1071409","article-title":"Molecular Biology and Genetics of Embryonic Eyelid Development","volume":"37","author":"Rubinstein","year":"2016","journal-title":"Ophthalmic Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/ng1070","article-title":"IASPP Oncoprotein Is a Key Inhibitor of P53 Conserved from Worm to Human","volume":"33","author":"Bergamaschi","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s10495-012-0728-z","article-title":"IASPP Inhibits P53-Independent Apoptosis by Inhibiting Transcriptional Activity of P63\/P73 on Promoters of Proapoptotic Genes","volume":"17","author":"Cai","year":"2012","journal-title":"Apoptosis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12943-025-02338-2","article-title":"Epithelial-to-Mesenchymal Transition (EMT) and Cancer Metastasis: The Status Quo of Methods and Experimental Models 2025","volume":"24","author":"Allgayer","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0092-8674(00)00211-7","article-title":"Negative Regulation of BMP\/Smad Signaling by Tob in Osteoblasts","volume":"103","author":"Yoshida","year":"2000","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"a022137","DOI":"10.1101\/cshperspect.a022137","article-title":"Signaling Cross Talk between TGF-\u03b2\/Smad and Other Signaling Pathways","volume":"9","author":"Luo","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hachana, S., and Larriv\u00e9e, B. (2022). TGF-\u03b2 Superfamily Signaling in the Eye: Implications for Ocular Pathologies. Cells, 11.","DOI":"10.3390\/cells11152336"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1242\/dev.034082","article-title":"FGF-Regulated BMP Signaling Is Required for Eyelid Closure and to Specify Conjunctival Epithelial Cell Fate","volume":"136","author":"Huang","year":"2009","journal-title":"Development"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1152\/physrev.2003.83.3.835","article-title":"Regulation of Wound Healing by Growth Factors and Cytokines","volume":"83","author":"Werner","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1126\/science.7618084","article-title":"Targeted Disruption of Mouse EGF Receptor: Effect of Genetic Background on Mutant Phenotype","volume":"269","author":"Threadgill","year":"1995","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nri910","article-title":"NF-KappaB Regulation in the Immune System","volume":"2","author":"Li","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/BJ20101220","article-title":"P65 Controls NF-\u039aB Activity by Regulating Cellular Localization of I\u03baB\u03b2","volume":"434","author":"Valovka","year":"2011","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/S0960-9822(95)00183-7","article-title":"High-Frequency Developmental Abnormalities in P53-Deficient Mice","volume":"5","author":"Armstrong","year":"1995","journal-title":"Curr. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1007\/s000180050180","article-title":"Integrin-Mediated Signal Transduction","volume":"54","author":"Longhurst","year":"1998","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Piwko-Czuchra, A., Koegel, H., Meyer, H., Bauer, M., Werner, S., Brakebusch, C., and F\u00e4ssler, R. (2009). Beta1 Integrin-Mediated Adhesion Signalling Is Essential for Epidermal Progenitor Cell Expansion. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005488"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1101\/gad.14.13.1553","article-title":"CBP\/P300 in Cell Growth, Transformation, and Development","volume":"14","author":"Goodman","year":"2000","journal-title":"Genes Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6991\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:17:10Z","timestamp":1785835030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6991"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":56,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156991"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156991","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}