{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:17:48Z","timestamp":1778645868235,"version":"3.51.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS104038"],"award-info":[{"award-number":["R01NS104038"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011781","name":"Shriners Hospitals for Children","doi-asserted-by":"publisher","award":["86100"],"award-info":[{"award-number":["86100"]}],"id":[{"id":"10.13039\/100011781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011781","name":"Shriners Hospitals for Children","doi-asserted-by":"publisher","award":["85109"],"award-info":[{"award-number":["85109"]}],"id":[{"id":"10.13039\/100011781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR068429-01"],"award-info":[{"award-number":["R01AR068429-01"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32HD098061"],"award-info":[{"award-number":["T32HD098061"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003206","name":"Alberta Children's Hospital Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003206","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD) and compared their phenotypes and magnetic resonance imaging (MRI) to ascertain how MPP5 DNV leads to GDD. All three patients with MPP5 DNV experienced GDD with language delay\/regression and behavioral changes. MRI ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on the developing brain were assessed by creating a heterozygous conditional knock out (het CKO) murine model with central nervous system (CNS)-specific Nestin-Cre drivers. In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared with wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression\/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa224","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T11:14:45Z","timestamp":1602760485000},"page":"3388-3401","source":"Crossref","is-referenced-by-count":8,"title":["<i>De novo<\/i> variants in <i>MPP5<\/i> cause global developmental delay and behavioral changes"],"prefix":"10.1093","volume":"29","author":[{"given":"Noelle","family":"Sterling","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna R","family":"Duncan","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raehee","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"Koolen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahai","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seo-Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul J","family":"Benke","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics, Joe DiMaggio Children\u2019s Hospital, Hollywood, FL 33021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia E","family":"Grant","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Radiology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casie A","family":"Genetti","sequence":"additional","affiliation":[{"name":"Division of Genetics & Genomics, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace E","family":"VanNoy","sequence":"additional","affiliation":[{"name":"Division of Genetics & Genomics, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Juusola","sequence":"additional","affiliation":[{"name":"Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsty","family":"McWalter","sequence":"additional","affiliation":[{"name":"Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jillian S","family":"Parboosingh","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan E","family":"Lamont","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois P","family":"Bernier","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J","family":"Harris","sequence":"additional","affiliation":[{"name":"Division of Genetics & Genomics, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander P A","family":"Stegmann","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"},{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A Micheil","family":"Innes","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seonhee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pankaj B","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Division of Genetics & Genomics, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"2021031106304920600_ref1","doi-asserted-by":"crossref","first-page":"11425","DOI":"10.1074\/jbc.275.15.11425","article-title":"Molecular cloning and characterization of pals, proteins associated with mLin-7","volume":"275","author":"Kamberov","year":"2000","journal-title":"J. Biol. 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