2. Academic Validation
  3. Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism

Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism

  • Ann Neurol. 2021 Jul;90(1):143-158. doi: 10.1002/ana.26127.
Anne Schänzer # 1,  Melanie T Achleitner # 2,  Dietrich Trümbach 3 4,  Laurence Hubert 5,  Arnold Munnich 5,  Barbara Ahlemeyer 6,  Maha M AlAbdulrahim 7,  Philipp A Greif 8,  Sebastian Vosberg 8 9,  Blake Hummer 10,  René G Feichtinger 2,  Johannes A Mayr 2,  Saskia B Wortmann 2 11,  Heidi Aichner 12,  Sabine Rudnik-Schöneborn 13,  Anna Ruiz 14,  Elisabeth Gabau 15,  Jacobo Pérez Sánchez 15,  Sian Ellard 16 17,  Tessa Homfray 18,  Karen L Stals 16,  Wolfgang Wurst 3 19 20 21,  Bernd A Neubauer 22,  Till Acker 1,  Stefan K Bohlander 23,  Cédric Asensio 10,  Claude Besmond 5,  Fowzan S Alkuraya 24,  Moenaldeen D AlSayed 25,  Andreas Hahn # 22,  Axel Weber # 26
Affiliations

Affiliations

  • 1 Institute of Neuropathology, Justus-Liebig-University, Giessen, Germany.
  • 2 University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
  • 3 Institute of Developmental Genetics, Helmholtz Center, Munich, Germany.
  • 4 Institute of Metabolism and Cell Death, Helmholtz Center, Munich, Germany.
  • 5 Inserm UMR1163, Imagine Institute, Tanslational Genetics, Université de Paris, Paris, France.
  • 6 Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Giessen, Germany.
  • 7 King Abdullah Bin Abdulaziz University Hospital, Riyadh, Saudi Arabia.
  • 8 Experimental Leukemia and Lymphoma Research Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
  • 9 German Cancer Research Centre (DKFZ), Heidelberg, Germany.
  • 10 Molecular and Cellular Biophysics Program, Department of Biological Sciences, University of Denver, Denver, CO, USA.
  • 11 Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands.
  • 12 Department of Pediatrics, Academic Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch, Austria.
  • 13 Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
  • 14 Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
  • 15 Paediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
  • 16 Genomic Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
  • 17 College of Medicine and Health, University of Exeter, Exeter, UK.
  • 18 Saint George's University Hospital and Royal Brompton Hospital, London, UK.
  • 19 Chair of Developmental Genetics, Faculty of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
  • 20 Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Munich, Germany.
  • 21 Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität, Munich, Germany.
  • 22 Department of Child Neurology, Justus-Liebig-University, Giessen, Germany.
  • 23 Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
  • 24 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 25 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 26 Institute of Human Genetics, Justus-Liebig-University, Giessen, Germany.
  • # Contributed equally.
PMID: 33999436 DOI: 10.1002/ana.26127
Abstract

Objective: 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.

Methods: 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.

Results: 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.

Interpretation: 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. ANN NEUROL 2021;90:149-164.

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