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Title: Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification
Author: Schottlaender, Lucia V.
Abeti, Rosella
Jaunmuktane, Zane
Macmillan, Carol
Chelban, Viorica
O'Callaghan, Benjamin
McKinley, John
Maroofian, Reza
Efthymiou, Stepanie
Athanasiou Fragkouli, Alkyoni
Forbes, Raeburn
Soutar, Marc P.M.
Livingston, John H.
Kalmar, Bernadett
Swayne, Orlando
Hotton, Gary
SYNAPS Study Group
Pittman, Alan
Mendes de Oliveira, João Ricardo
de Grandis, Maria
Richard Loendt, Angela
Launchbury, Francesca
Althonayan, Juri
McDonnell, Gavin
Carr, Aisling S.
Khan, Suliman
Beetz, Christian
Bisgin, Atil
Tug Bozdogan, Sevcan
Begtrup, Amber
Torti, Erin
Greensmith, Linda
Giunti, Paola
Morrison, Patrick J.
Brandner, Sebastian
Aurrand Lions, Michael
Houlden, Henry
Cormand Rifà, Bru
Keywords: Calcificació
Malalties neurodegeneratives
Neurodegenerative Diseases
Issue Date: 5-Mar-2020
Publisher: Cell Press
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.
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It is part of: American Journal of Human Genetics, 2020, vol. 106, num. 3, p. 412-421
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ISSN: 0002-9297
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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