ArticleAmerican journal of human genetics2020
Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 82 citations in OpenAlex.
- Brain calcification-associated JAM2 pathogenic mutations impair JAM2-JAM3 tight junction structure and the blood-brain barrier integrity.Brain pathology (Zurich, Switzerland) · 2026Article
- Multi-Omics Integration Reveals That SN-011 Targets JUNB to Upregulate ADGRE5 and Restore Vascular Endothelial Cell Communication in Ischemic Stroke.Chemical biology & drug design · 2026Article
- Phenotypic Refinement of ESAM-Related Tight-Junctionopathy: Novel Genetic and Ocular Findings and Literature Review.Molecular genetics & genomic medicine · 2026Review
- Neuro-Immune Crosstalk: Molecular Mechanisms, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2026Review
- Experimental Primary Brain Calcification Model and Its Application to Pathogenesis Mechanism Analysis and Therapeutic Research.Neurology international · 2025Review
- RRP12 Variants Are Associated With Autosomal Recessive Brain Calcifications.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Mutation spectrum and clinical features of MYORG in Iranian patients with Primary Familial Brain Calcification (PFBC).Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Computational molecular characterization of a novel SLC20A2 variant associated with primary familial brain calcification.Scientific reports · 2025Article
- The Triad of Blood-Brain Barrier Integrity: Endothelial Cells, Astrocytes, and Pericytes in Perinatal Stroke Pathophysiology.International journal of molecular sciences · 2025Review
- Novel homozygous ESAM variants in two families with perinatal strokes showing variable neuroradiologic and clinical findings.Journal of human genetics · 2025Article
- A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease.Scientific reports · 2025Article
- A robust transfer learning approach for high-dimensional linear regression to support integration of multi-source gene expression data.PLoS computational biology · 2025Article
- Astrocytes in Primary Familial Brain Calcification (PFBC): Emphasis on the Importance of Induced Pluripotent Stem Cell-Derived Human Astrocyte Models.Advances in experimental medicine and biology · 2025Review
- Fahr's Syndrome with Pseudohypoparathyroidism: Oral Features and Genetic Insights.International journal of molecular sciences · 2024Article
- JAM2 variants can be more common in primary familial brain calcification (PFBC) cases than those appear; may be due to a founder mutation.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Upstream open reading frame-introducing variants in patients with primary familial brain calcification.European journal of human genetics : EJHG · 2024Article
- Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.Nature communications · 2024Article
- The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial.Orphanet journal of rare diseases · 2024Article
- The Association between Intracranial Calcifications and Symptoms in Patients with Primary Familial Brain Calcification.Journal of clinical medicine · 2024Article
- One Train May Hide Another: Two Cases of Co-Occurring Primary Familial Brain Calcification and Alzheimer's Disease.Journal of molecular neuroscience : MN · 2024Article
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37 authors at 12 institutions in 8 countries.
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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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