PMID- 33073849 OWN - NLM STAT- MEDLINE DCOM- 20210830 LR - 20211022 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 29 IP - 20 DP - 2020 Dec 18 TI - De novo variants in MPP5 cause global developmental delay and behavioral changes. PG - 3388-3401 LID - 10.1093/hmg/ddaa224 [doi] AB - 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. CI - (c) The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Sterling, Noelle AU - Sterling N AD - Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA. FAU - Duncan, Anna R AU - Duncan AR AD - Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. FAU - Park, Raehee AU - Park R AD - Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA. FAU - Koolen, David A AU - Koolen DA AD - Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands. FAU - Shi, Jiahai AU - Shi J AD - Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR. FAU - Cho, Seo-Hee AU - Cho SH AD - Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA. FAU - Benke, Paul J AU - Benke PJ AD - Division of Clinical Genetics, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA. FAU - Grant, Patricia E AU - Grant PE AD - Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. AD - Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA. FAU - Genetti, Casie A AU - Genetti CA AD - Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. AD - Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. FAU - VanNoy, Grace E AU - VanNoy GE AD - Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. AD - Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. FAU - Juusola, Jane AU - Juusola J AD - Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA. FAU - McWalter, Kirsty AU - McWalter K AD - Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA. FAU - Parboosingh, Jillian S AU - Parboosingh JS AD - Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada. FAU - Lamont, Ryan E AU - Lamont RE AD - Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada. FAU - Bernier, Francois P AU - Bernier FP AD - Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada. FAU - Smith, Christopher AU - Smith C AD - Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada. FAU - Harris, David J AU - Harris DJ AD - Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. FAU - Stegmann, Alexander P A AU - Stegmann APA AD - Department of Clinical Genetics, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands. AD - Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. FAU - Innes, A Micheil AU - Innes AM AD - Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1A4, Canada. FAU - Kim, Seonhee AU - Kim S AD - Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine. Temple University, Philadelphia, PA, 19140, USA. FAU - Agrawal, Pankaj B AU - Agrawal PB AD - Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. AD - Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. AD - Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. LA - eng GR - R01 AR068429/AR/NIAMS NIH HHS/United States GR - R01 EY020578/EY/NEI NIH HHS/United States GR - R01 NS104038/NS/NINDS NIH HHS/United States GR - T32 HD098061/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 0 (Membrane Proteins) RN - EC 2.7.4.4 (Nucleoside-Phosphate Kinase) RN - EC 2.7.4.8 (MPP5 protein, human) RN - EC 2.7.4.8 (Mpp5 protein, mouse) SB - IM MH - Adolescent MH - Adult MH - Animals MH - Child MH - Developmental Disabilities/*etiology/metabolism/pathology MH - Female MH - Humans MH - Male MH - Membrane Proteins/*genetics/*physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - *Mutation MH - Nervous System Diseases/*etiology/metabolism/pathology MH - Nucleoside-Phosphate Kinase/*genetics/*physiology MH - Young Adult PMC - PMC7906781 EDAT- 2020/10/20 06:00 MHDA- 2021/08/31 06:00 PMCR- 2021/10/19 CRDT- 2020/10/19 08:41 PHST- 2020/05/29 00:00 [received] PHST- 2020/08/27 00:00 [revised] PHST- 2020/10/11 00:00 [accepted] PHST- 2020/10/20 06:00 [pubmed] PHST- 2021/08/31 06:00 [medline] PHST- 2020/10/19 08:41 [entrez] PHST- 2021/10/19 00:00 [pmc-release] AID - 5928217 [pii] AID - ddaa224 [pii] AID - 10.1093/hmg/ddaa224 [doi] PST - ppublish SO - Hum Mol Genet. 2020 Dec 18;29(20):3388-3401. doi: 10.1093/hmg/ddaa224.