eprintid: 10093228 rev_number: 47 eprint_status: archive userid: 608 dir: disk0/10/09/32/28 datestamp: 2020-03-12 14:33:37 lastmod: 2021-09-18 21:50:37 status_changed: 2020-03-12 14:33:37 type: article metadata_visibility: show creators_name: Schottlaender, LV creators_name: Abeti, R creators_name: Jaunmuktane, Z creators_name: Macmillan, C creators_name: Chelban, V creators_name: O'Callaghan, B creators_name: McKinley, J creators_name: Maroofian, R creators_name: Efthymiou, S creators_name: Athanasiou-Fragkouli, A creators_name: Forbes, R creators_name: Soutar, MPM creators_name: Livingston, JH creators_name: Kalmar, B creators_name: Swayne, O creators_name: Hotton, G creators_name: SYNAPS Study Group, creators_name: Pittman, A creators_name: Mendes de Oliveira, JR creators_name: de Grandis, M creators_name: Richard-Loendt, A creators_name: Launchbury, F creators_name: Althonayan, J creators_name: McDonnell, G creators_name: Carr, A creators_name: Khan, S creators_name: Beetz, C creators_name: Bisgin, A creators_name: Tug Bozdogan, S creators_name: Begtrup, A creators_name: Torti, E creators_name: Greensmith, L creators_name: Giunti, P creators_name: Morrison, PJ creators_name: Brandner, S creators_name: Aurrand-Lions, M creators_name: Houlden, H title: Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification ispublished: pub subjects: UCH divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 divisions: F85 divisions: F86 divisions: C08 divisions: D09 keywords: Fahr disease, JAM2, JAM3, MYORG, OCLN, SLC20A2, familial idiopathic basal ganglia calcification, knock out mouse model, primary familial brain calcification, recessive brain calcification note: Copyright © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 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. date: 2020-03-05 date_type: published official_url: https://doi.org/10.1016/j.ajhg.2020.02.007 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1771145 doi: 10.1016/j.ajhg.2020.02.007 pii: S0002-9297(20)30049-5 lyricists_name: Abeti, Rosella lyricists_name: Brandner, Sebastian lyricists_name: Chelban, Viorica lyricists_name: Efthymiou, Stephanie lyricists_name: Giunti, Paola lyricists_name: Greensmith, Linda lyricists_name: Houlden, Henry lyricists_name: Jaunmuktane, Zane lyricists_name: Kalmar, Bernadett lyricists_name: Maroofian, Reza lyricists_name: O'Callaghan, Benjamin lyricists_name: Richard-Londt, Angela lyricists_name: Schottlaender, Lucia lyricists_name: Soutar, Marc lyricists_name: Swayne, Orlando lyricists_id: RABET32 lyricists_id: SBRAN30 lyricists_id: VCHEL09 lyricists_id: SEFTH99 lyricists_id: PGIUN65 lyricists_id: LGREE07 lyricists_id: HJHOU44 lyricists_id: ZJAUN70 lyricists_id: BKALM92 lyricists_id: RMARO97 lyricists_id: BOCAL97 lyricists_id: ACRIC49 lyricists_id: LSCHO03 lyricists_id: MSOUT43 lyricists_id: OBCSW66 actors_name: Allington-Smith, Dominic actors_id: DAALL44 actors_role: owner full_text_status: public publication: AJHG volume: 106 number: 3 pagerange: 412-421 event_location: United States citation: Schottlaender, LV; Abeti, R; Jaunmuktane, Z; Macmillan, C; Chelban, V; O'Callaghan, B; McKinley, J; ... Houlden, H; + view all <#> Schottlaender, LV; Abeti, R; Jaunmuktane, Z; Macmillan, C; Chelban, V; O'Callaghan, B; McKinley, J; Maroofian, R; Efthymiou, S; Athanasiou-Fragkouli, A; Forbes, R; Soutar, MPM; Livingston, JH; Kalmar, B; Swayne, O; Hotton, G; SYNAPS Study Group; Pittman, A; Mendes de Oliveira, JR; de Grandis, M; Richard-Loendt, A; Launchbury, F; Althonayan, J; McDonnell, G; Carr, A; Khan, S; Beetz, C; Bisgin, A; Tug Bozdogan, S; Begtrup, A; Torti, E; Greensmith, L; Giunti, P; Morrison, PJ; Brandner, S; Aurrand-Lions, M; Houlden, H; - view fewer <#> (2020) Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification. AJHG , 106 (3) pp. 412-421. 10.1016/j.ajhg.2020.02.007 <https://doi.org/10.1016/j.ajhg.2020.02.007>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10093228/14/Brandner_1-s2.0-S0002929720300495-main.pdf