Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 106, Issue 3, Pages 412-421Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.02.007
Keywords
-
Categories
Funding
- Medical Research Council (MRC) [MR/S01165X/1, MR/S005021/1]
- Wellcome Trust (Synaptopathies Strategic Award) [WT093205MA, WT104033AIA]
- Rosetree Trust
- Ataxia UK
- MSA Trust
- Brain Research UK
- Sparks GOSH Charity
- Muscular Dystrophy UK (MDUK)
- Muscular Dystrophy Association (MDA USA)
- National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre
- Dementia Biomedical Research Unit
- CNP
- CAPES
- DECIT-MS
- National Institute for Health Research (NIHR) award
- MRC [MR/S005021/1, MR/S01165X/1] Funding Source: UKRI
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available