De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling.

Autor:	Morleo M; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy. Electronic address: morleo@tigem.it., Venditti R; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II,' Medical School, Naples, Italy., Theodorou E; Center for Genomic Medicine, Divisions of Pediatric Hematology/Oncology and Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Briere LC; Center for Genomic Medicine, Divisions of Pediatric Hematology/Oncology and Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Rosello M; Sorbonne Université, INSERM U968, CNRS UMR 7210, Institut de la Vision, Paris, France., Tirozzi A; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy; Department of Epidemiology and Prevention, IRCCS NEUROMED, Pozzilli, Italy., Tammaro R; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy., Al-Badri N; Sorbonne Université, INSERM U968, CNRS UMR 7210, Institut de la Vision, Paris, France., High FA; Division of Medical Genetics & Metabolism, Massachusetts General Hospital for Children, Boston, MA 02114, USA., Shi J; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Putti E; Sorbonne Université, INSERM U968, CNRS UMR 7210, Institut de la Vision, Paris, France., Ferrante L; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy., Cetrangolo V; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy., Torella A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy., Walker MA; Department of Neurology, Division of Neurogenetics, Child Neurology, Massachusetts General Hospital, Boston, MA, USA., Tenconi R; Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, Padova, Italy., Iascone M; Medical Genetics, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy., Mei D; Meyer Children's Hospital IRCCS, Neuroscience Department, Florence, Italy., Guerrini R; Meyer Children's Hospital IRCCS, Neuroscience Department, Florence, Italy., van der Smagt J; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Kroes HY; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., van Gassen KLI; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Bilal M; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Umair M; Medical Genomics Research Department, King Abdullah International Medical Research Center & King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia., Pingault V; Service de Médecine Génomique des Maladies Rares, et Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France., Attie-Bitach T; Service de Médecine Génomique des Maladies Rares, et Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France., Amiel J; Service de Médecine Génomique des Maladies Rares, et Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France., Ejaz R; Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, Hamilton, ON, Canada., Rodan L; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA., Zollino M; Institute of Medical Genetics, A. Gemelli School of Medicine, Catholic University of the Sacred Heart, Rome, Italy., Agrawal PB; Divisions of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Del Bene F; Sorbonne Université, INSERM U968, CNRS UMR 7210, Institut de la Vision, Paris, France., Nigro V; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy., Sweetser DA; Center for Genomic Medicine, Divisions of Pediatric Hematology/Oncology and Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: dsweetser@mgh.harvard.edu., Franco B; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, Naples, Italy; Medical Genetics, Department of Translational Medicine, University of Naples 'Federico II,' Via Sergio Pansini, 80131 Naples, Italy.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Aug 03; Vol. 110 (8), pp. 1377-1393. Date of Electronic Publication: 2023 Jul 13.
DOI:	10.1016/j.ajhg.2023.06.012
Abstrakt:	Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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