2. Academic Validation
  3. Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation

Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation

  • Am J Hum Genet. 2022 May 5;109(5):909-927. doi: 10.1016/j.ajhg.2022.03.010.
Marion Coolen 1,  Nami Altin 2,  Karthyayani Rajamani 2,  Eva Pereira 2,  Karine Siquier-Pernet 2,  Emilia Puig Lombardi 3,  Nadjeda Moreno 4,  Giulia Barcia 5,  Marianne Yvert 6,  Annie Laquerrière 7,  Aurore Pouliet 8,  Patrick Nitschké 3,  Nathalie Boddaert 9,  Antonio Rausell 10,  Féréchté Razavi 11,  Alexandra Afenjar 12,  Thierry Billette de Villemeur 13,  Almundher Al-Maawali 14,  Khalid Al-Thihli 14,  Julia Baptista 15,  Ana Beleza-Meireles 16,  Catherine Garel 17,  Marine Legendre 18,  Antoinette Gelot 19,  Lydie Burglen 20,  Sébastien Moutton 6,  Vincent Cantagrel 21
Affiliations

Affiliations

  • 1 Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France. Electronic address: marion.coolen@inserm.fr.
  • 2 Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France.
  • 3 Université Paris Cité, Bioinformatics Core Facility, Imagine Institute, INSERM UMR 1163, Paris 75015, France.
  • 4 HDBR Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 5 Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France; Département de Génétique Médicale, AP-HP, Hôpital Necker-Enfants Malades, Paris 75015, France.
  • 6 Centre Pluridisciplinaire de Diagnostic Prénatal, Pôle Mère Enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence 33400, France.
  • 7 Normandie Univ, UNIROUEN, INSERM U1245; Rouen University Hospital, Department of Pathology, Normandy Centre for Genomic and Personalized Medicine, Rouen 76183, France.
  • 8 Université Paris Cité, Genomics Platform, Imagine Institute, INSERM UMR 1163, Paris 75015, France.
  • 9 Département de Radiologie Pédiatrique, INSERM UMR 1163 and INSERM U1299, Institut Imagine, AP-HP, Hôpital Necker-Enfants Malades, Paris 75015, France.
  • 10 Université Paris Cité, INSERM UMR1163, Imagine Institute, Clinical Bioinformatics Laboratory and Molecular Genetics Service, Service de Médecine Génomique des Maladies Rares, AP-HP, Hôpital Necker-Enfants Malades, Paris 75015, France.
  • 11 Unité d'Embryofœtopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France.
  • 12 Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, Paris 75012, France.
  • 13 Sorbonne Université, Service de Neuropédiatrie - Pathologie du Développement, Centre de Référence Déficiences Intellectuelles de Causes Rares et Polyhandicap, Hôpital Trousseau AP-HP, Paris 75012, France.
  • 14 Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat 123, Oman.
  • 15 Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth PL6 8BT, UK.
  • 16 Clinical Genetics Department, University Hospitals Bristol and Weston, Bristol BS1 3NU, UK.
  • 17 Service de Radiologie Pédiatrique, Hôpital Armand-Trousseau, Médecine Sorbonne Université, AP-HP, Paris 75012, France.
  • 18 Service de Génétique Médicale, CHU Bordeaux, Pellegrin Hospital, Bordeaux 33300, France.
  • 19 Neuropathology, Department of Pathology, Trousseau Hospital, AP-HP, Paris 75012, France; INMED, Aix-Marseille University, INSERM UMR 1249, Marseille 13009, France.
  • 20 Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France; Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, Paris 75012, France.
  • 21 Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France. Electronic address: vincent.cantagrel@inserm.fr.
PMID: 35390279 DOI: 10.1016/j.ajhg.2022.03.010
Abstract

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Keywords

PRDM13; Purkinje cells; brainstem; cerebellum; inferior olive nuclei; neurodevelopment; neuronal specification; olivopontocerebellar hypoplasia; zebrafish.

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