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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification
American Journal of Human Genetics, Volume 106, No. 3, Year 2020
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Description
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. © 2020 The Authors
Authors & Co-Authors
Schottlaender, Lucía V.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Argentina, Buenos Aires
Fundacion Para la Lucha Contra Las Enfermedades Neurologicas de la Infancia
Jaunmuktane, Zane T.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
University College London Hospitals Nhs Foundation Trust
Chelban, Viorica
United Kingdom, London
Ucl Queen Square Institute of Neurology
Maroofian, Reza
United Kingdom, London
Ucl Queen Square Institute of Neurology
Efthymiou, Stephanie
United Kingdom, London
Ucl Queen Square Institute of Neurology
Athanasiou-Fragkouli, Alkyoni
United Kingdom, London
Ucl Queen Square Institute of Neurology
Livingston, John H.
United Kingdom, Leeds
Leeds Teaching Hospitals Nhs Trust
Kalmár, Bernadett
United Kingdom, London
Ucl Queen Square Institute of Neurology
Groppa, Stanislav A.
Unknown Affiliation
Karashova, Blagovesta Marinova
Unknown Affiliation
Nachbauer, Wolfgang
Unknown Affiliation
Boesch, Sylvia M.
Unknown Affiliation
Arning, Larissa
Unknown Affiliation
Timmann, Dagmar
Unknown Affiliation
Cormand, Bru
Unknown Affiliation
Pérez-Dueñas, Belén
Unknown Affiliation
Di Rosa, Gabriella
Unknown Affiliation
Goraya, Jatinder Singh
Unknown Affiliation
Sultan, Tipu
Unknown Affiliation
Mine, Jyun
Unknown Affiliation
Avdjieva - Tzavella, Daniela Mircheva
Unknown Affiliation
Kathom, Hadil Mohamed
Unknown Affiliation
Tincheva, Radka Stefanova
Unknown Affiliation
Banu, Selina H.
Unknown Affiliation
Pineda-Marfà, Mercedes
Unknown Affiliation
Veggiotti, Pierangelo
Unknown Affiliation
Ferrari, Michel Dominique
Unknown Affiliation
Verrottï, Alberto
Unknown Affiliation
Marseglia, Gian Luigi
Unknown Affiliation
Savasta, Salvatore M.
Unknown Affiliation
García-Silva, Mayte
Unknown Affiliation
Ruiz, Alfons Macaya
Unknown Affiliation
Garavaglia, Barbara M.
Unknown Affiliation
Borgione, Eugenia
Unknown Affiliation
Portaro, Simona
Unknown Affiliation
Sanchez, Benigno Monteagudo
Unknown Affiliation
Boles, Richard G.
Unknown Affiliation
Papacostas, Savvas S.
Unknown Affiliation
Vikelis, Michail
Unknown Affiliation
Papanicolaou, Eleni Zamba
Unknown Affiliation
Dardiotis, Efthymios
Unknown Affiliation
Maqbool, Shazia
Unknown Affiliation
Ibrahim, Shahnaz Hamid
Unknown Affiliation
Kirmani, Salman
Unknown Affiliation
Rana, Nuzhat Noureen
Unknown Affiliation
Atawneh, Osama M.
Unknown Affiliation
Koutsis, Georgios
Unknown Affiliation
Breza, Marianthi
Unknown Affiliation
Mangano, Salvatore
Unknown Affiliation
Scuderi, Carmela
Unknown Affiliation
Morello, Giovanna
Unknown Affiliation
Stojkovic, Tanya
Unknown Affiliation
Heimer, Gali
Unknown Affiliation
Dauvilliers, Yves A.
Unknown Affiliation
Striano, Pasquale
Unknown Affiliation
Al-Khawaja, Issam
Unknown Affiliation
Al-Mutairi, Fuad
Unknown Affiliation
Hamed, Sherifa Ahmed
Unknown Affiliation
Pittman, Alan Michael
United Kingdom, London
Ucl Queen Square Institute of Neurology
McDonnell, Gavin V.
United Kingdom, Belfast
Royal Victoria Hospital Belfast
Carr, Aisling S.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Khan, Suliman
Germany, Rostock
Centogene ag
Beetz, Christian
Germany, Rostock
Centogene ag
Begtrup, Amber G.
United States, Gaithersburg
Genedx, Inc.
Torti, Erin E.
United States, Gaithersburg
Genedx, Inc.
Greensmith, Linda
United Kingdom, London
Ucl Queen Square Institute of Neurology
Giunti, Paola
United Kingdom, London
Ucl Queen Square Institute of Neurology
Morrison, Patrick J.
United Kingdom, Belfast
Queen's University Belfast
Brandner, Sebastian G.P.
United Kingdom, London
University College London Hospitals Nhs Foundation Trust
Houlden, Henry H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Statistics
Citations: 40
Authors: 70
Affiliations: 16
Identifiers
Doi:
10.1016/j.ajhg.2020.02.007
ISSN:
00029297
Research Areas
Genetics And Genomics
Health System And Policy
Mental Health