6533b823fe1ef96bd127edd9
RESEARCH PRODUCT
Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification
Gali HeimerNuzhat RanaAmber BegtrupMaria De GrandisTanya StojkovicZane JaunmuktaneZane JaunmuktaneAisling CarrTipu SultanSelina BanuWolfgang NachbauerHadil KathomRichard BolesJoão Ricardo Mendes De OliveiraPaola GiuntiRadka TinchevaBenjamin O’callaghanJatinder S. GorayaGeorge KoutsisEleni Zamba PapanicolaouSimona PortaroRosella AbetiBru CormandMassimi ZolloMarianthi BrezaMichel D. FerrariAtil BisginSuliman KhanAlfons Macaya RuizMarc P.m. SoutarFuad Al-mutairiReza MaroofianAngela Richard-loendtBenigno Monteagudo SanchezDaniela AvdjievaJuri AlthonayanBlagovesta Marinova KarashovaMichel Aurrand-lionsMichail VikelisDagmar TimmannHenry HouldenS BoeschSalman KirmaniPasquale StrianoHamed SherifaAlkyoni Athanasiou-fragkouliRaeburn B ForbesJun MineViorica ChelbanIssam Al-khawajaEfthimios DardiotisGabriella Di RosaGiovanna MorelloGary HottonSalvatore SavastaAlan PittmanShazia MaqboolBernardett KalmarAlberto VerrottiErin TortiChristian BeetzStephanie EfthymiouBarbara GaravagliaFrancesca LaunchburyEugenia BorgioneJohn MckinleySalvatore ManganoLucia SchottlaenderLucia SchottlaenderLucia SchottlaenderPierangelo VeggiottiJohn H. LivingstonShahnaz IbrahimMayte García-silvaOrlando B.c. SwayneBelen Pérez-dueñasCarol MacmillanMercedes Pineda-marfa’Larissa ArningGavin McdonnellCarmela ScuderiSavvas PapacostasGian Luigi MarsegliaOsama AtawnehStanislav GroppaLinda GreensmithPatrick J. MorrisonSevcan Tug BozdoganSebastian BrandnerYves A. Dauvillierssubject
0301 basic medicineMaleCerebellumPathology[SDV]Life Sciences [q-bio]recessive brain calcificationMice0302 clinical medicineCognitive declineAge of OnsetChildGenetics (clinical)Exome sequencingComputingMilieux_MISCELLANEOUSBrain Diseasesprimary familial brain calcificationMalalties neurodegenerativesBrainFahr diseaseCalcinosisOCLNNeurodegenerative DiseasesHuman brainMiddle AgedPedigree[SDV] Life Sciences [q-bio]medicine.anatomical_structureKnockout mouseFemalemedicine.symptomAdultmedicine.medical_specialtyAdolescentGenes RecessiveNeuropathologyBiologyCalcificacióCalcification03 medical and health sciencesBasal Ganglia DiseasesReportGeneticsmedicineAnimalsHumansAllelesSLC20A2Cerebellar ataxiaknock out mouse modelmedicine.diseaseJAM2030104 developmental biologyFahr disease; familial idiopathic basal ganglia calcification; JAM2; JAM3; knock out mouse model; MYORG; OCLN; primary familial brain calcification; recessive brain calcification; SLC20A2familial idiopathic basal ganglia calcificationJAM3MYORGXenotropic and Polytropic Retrovirus ReceptorCell Adhesion Molecules030217 neurology & neurosurgeryCalcificationdescription
International audience; 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-03-01 |