Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism
Schänzer, Anne (Institute of Neuropathology, Justus-Liebig-University, Giessen, Germany)
Achleitner, Melanie T. (University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria)
Trümbach, Dietrich (Institute of Metabolism and Cell Death, Helmholtz Center, Munich, Germany)
Hubert, Laurence (Inserm UMR1163, Imagine Institute, Tanslational Genetics, Université de Paris, Paris, France)
Munnich, Arnold (Inserm UMR1163, Imagine Institute, Tanslational Genetics, Université de Paris, Paris, France)
Ahlemeyer, Barbara (Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Giessen, Germany)
AlAbdulrahim, Maha M. (King Abdullah Bin Abdulaziz University Hospital, Riyadh, Saudi Arabia)
Greif, Philipp A. (Ludwig-Maximilians-University of Munich. Department of Medicine III)
Vosberg, Sebastian (German Cancer Research Centre (DKFZ))
Hummer, Blake (Molecular and Cellular Biophysics Program, Department of Biological Sciences, University of Denver, Denver, CO, USA)
Feichtinger, René G. (University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria)
Mayr, Johannes A. (University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria)
Wortmann, Saskia B. (Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands)
Aichner, Heidi (Department of Pediatrics, Academic Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch, Austria)
Rudnik-Schöneborn, Sabine (Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria)
Ruiz, Anna (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Gabau, Elisabeth (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Pérez Sánchez, Jacobo (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Ellard, Sian (College of Medicine and Health, University of Exeter, Exeter, UK)
Homfray, Tessa (Saint George's University Hospital and Royal Brompton Hospital, London, UK)
Stals, Karen L. (Genomic Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK)
Wurst, Wolfgang (Ludwig-Maximilians-Universität München)
Neubauer, Bernd A. (Department of Child Neurology, Justus-Liebig-University, Giessen, Germany)
Acker, Till (Institute of Neuropathology, Justus-Liebig-University, Giessen, Germany)
Bohlander, Stefan K. (Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand)
Asensio, Cédric (Molecular and Cellular Biophysics Program, Department of Biological Sciences, University of Denver, Denver, CO, USA)
Besmond, Claude (Inserm UMR1163, Imagine Institute, Tanslational Genetics, Université de Paris, Paris, France)
Alkuraya, Fowzan S. (King Faisal Specialist Hospital & Research Center)
AlSayed, Moenaldeen D. (King Faisal Specialist Hospital and Research Centre (Aràbia Saudita))
Hahn, Andreas (Department of Child Neurology, Justus-Liebig-University, Giessen, Germany)
Weber, Axel (Institute of Human Genetics, Justus-Liebig- University, Giessen, Germany)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p. R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Annals of neurology, Vol. 90 (june 2021) , p. 143-158, ISSN 1531-8249

DOI: 10.1002/ana.26127
PMID: 33999436

16 p, 6.7 MB

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