2. Academic Validation
  3. Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification

  • Am J Hum Genet. 2020 Mar 5;106(3):412-421. doi: 10.1016/j.ajhg.2020.02.007.
Lucia V Schottlaender 1,  Rosella Abeti 2,  Zane Jaunmuktane 3,  Carol Macmillan 4,  Viorica Chelban 5,  Benjamin O'Callaghan 5,  John McKinley 6,  Reza Maroofian 5,  Stephanie Efthymiou 5,  Alkyoni Athanasiou-Fragkouli 5,  Raeburn Forbes 7,  Marc P M Soutar 8,  John H Livingston 9,  Bernardett Kalmar 5,  Orlando Swayne 10,  Gary Hotton 10,  SYNAPS Study Group 5,  Alan Pittman 5,  João Ricardo Mendes de Oliveira 11,  Maria de Grandis 12,  Angela Richard-Loendt 8,  Francesca Launchbury 8,  Juri Althonayan 2,  Gavin McDonnell 13,  Aisling Carr 14,  Suliman Khan 15,  Christian Beetz 15,  Atil Bisgin 16,  Sevcan Tug Bozdogan 16,  Amber Begtrup 17,  Erin Torti 17,  Linda Greensmith 5,  Paola Giunti 2,  Patrick J Morrison 18,  Sebastian Brandner 19,  Michel Aurrand-Lions 12,  Henry Houlden 20
Affiliations

Affiliations

  • 1 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, UK; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, WC1N 1EH London, UK; Argentine National Scientific and Technological Research Council (CONICET), C1425FQB Buenos Aires, Argentina; FLENI Neurological Research Institute, C1428 AQK Buenos Aires, Argentina.
  • 2 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, WC1N3BG London, UK.
  • 3 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, WC1N3BG London, UK; Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK.
  • 4 Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
  • 5 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, UK.
  • 6 Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles St, Dublin 7 DO7W7XF, Ireland; Regional Neurosciences Centre, Royal Victoria Hospital, Belfast BT12 6BA, UK.
  • 7 Neurology Centre, Southern HSC Trust, Craigavon Area Hospital, Portadown BT63 5QQ, UK.
  • 8 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
  • 9 Paediatric Neurology, The Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary, Leeds LS1 3EX, UK.
  • 10 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, WC1N3BG London, UK; The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
  • 11 Universidade Federal de Pernambuco, Departamento de Neuropsiquiatria, Recife 50670-901, Brazil.
  • 12 Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, 13009 Marseille, France.
  • 13 Regional Neurosciences Centre, Royal Victoria Hospital, Belfast BT12 6BA, UK.
  • 14 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, UK; The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
  • 15 CENTOGENE AG, Rostock 18055, Germany.
  • 16 Medical Genetics Department of Medical Faculty & AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Çukurova University, Adana 01330, Turkey.
  • 17 GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 18 Centre for Cancer Research and Cell Biology, Queens University, Belfast BT9 7AE, UK.
  • 19 Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK.
  • 20 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, UK; The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK; Neurogenetics Laboratory and Clinical Service, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Electronic address: [email protected].
PMID: 32142645 DOI: 10.1016/j.ajhg.2020.02.007
Abstract

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.

Keywords

Fahr disease; JAM2; JAM3; MYORG; OCLN; SLC20A2; familial idiopathic basal ganglia calcification; knock out mouse model; primary familial brain calcification; recessive brain calcification.

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