TIGHT JUNCTION MUTATIONS - keywords
tight junctions
references to tight junction mutations
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Abdel-Salam GM, Zaki MS, Saleem SN, Gaber KR (2008) Microcephaly, malformation of brain development and intracranial calcification in sibs: pseudo-TORCH or a new syndrome. Am J Med Genet A 146A(22):2929-36.
Abdel-Salam GMH, Esmail A, Nagy D, Abdel-Ghafar SF, Abdel-Hamid MS. Novel homozygous ESAM variants in two families with perinatal strokes showing variable neuroradiologic and clinical findings. J Hum Genet. 2025 Feb;70(2):67-74.
Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. NATURE REVIEWS | NEUROSCIENCE. VOLUME 7 | JANUARY 2006 41-53.
Akawi NA, Canpolat FE, White SM, Quilis-Esquerra J, Morales Sanchez M, Gamundi MJ, Mochida GH, Walsh CA, Ali BR, Al-Gazali L (2013) Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Hum Mutat 34(3):498-505.
Andersson EA, Rocha-Ferreira E, Hagberg H, Mallard C, Ek CJ. Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model. Cells. 2021 Jul 2;10(7):1677.
Brady ST, Siegel GJ (2012) BASIC NEUROCHEMISTRY: principles of molecular, cellular and medical neurobiology. Eighth edition. Elsevier.
Briggs TA, Wolf NI, D'Arrigo S, Ebinger F, Harting I, Dobyns WB, Livingston JH, Rice GI, Crooks D, Rowland-Hill CA, Squier W, Stoodley N, Pilz DT, Crow YJ (2008) Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype. Am J Med Genet A 146A(24):3173-80.
Cen Z, Chen Y, Chen S, Wang H, Yang D, Zhang H, Wu H, Wang L, Tang S, Ye J, Shen J, Wang H, Fu F, Chen X, Xie F, Liu P, Xu X, Cao J, Cai P, Pan Q, Li J, Yang W, Shan PF, Li Y, Liu JY, Zhang B, Luo W. Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification. Brain. 2020 Feb 1;143(2):491-502.
Engelhardt B (2003) Development of the blood-brain barrier. Cell Tissue Res 314:119–129.
Hashimoto Y, Greene C, Munnich A, Campbell M. The CLDN5 gene at the blood-brain barrier in health and disease. Fluids Barriers CNS. 2023 Mar 28;20(1):22.
Kozak I, Mochida GH, Lin DDM, Ali SM, Bosley TM. Spotlight on Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC). Eye Brain. 2024 Oct 23;16:55-63.
Meuwissen ME, Lequin MH, Bindels-de Heus K, Bruggenwirth HT, Knapen MF, Dalinghaus M, de Coo R, van Bever Y, Winkelman BH, Mancini GM (2013) ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome. Am J Med Genet A 161A:1376-80.
Mochida GH, Ganesh VS, Felie JM, Gleason D, Hill RS, Clapham KR, Rakiec D, Tan WH, Akawi N, Al-Saffar M, Partlow JN, Tinschert S, Barkovich AJ, Ali B, Al-Gazali L, Walsh CA (2010) A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet 87(6):882-9.
O'Driscoll MC, Daly SB, Urquhart JE, Black GC, Pilz DT, Brockmann K, McEntagart M, Abdel-Salam G, Zaki M, Wolf NI, Ladda RL, Sell S, D'Arrigo S, Squier W, Dobyns WB, Livingston JH, Crow YJ (2010) Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am J Hum Genet 87(3):354-64.
Saunders NR, Dziegielewska KM, Mollgard K, Habgood MD (2018). Physiology and molecular biology of barrier mechanisms in the fetal and neonatal brain. J. Physiol. 596, 5723–5756.
Steed E, Balda MS, Matter K (2010) Dynamics and functions of tight junctions. Trends in Cell Biology 20(3):142–149.
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MRI at 2 months
- band-like gray matter calcification: calcification surrounds vessels but spares the endothelium; Purkinje cells are calcified
- frontoparietal polymicrogyria
- progressive microcephaly with simplified gyral pattern
Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is an autosomal recessive disorder featuring early-onset seizures, severe microcephaly and developmental arrest, coupled to bilateral, symmetrical polymicrogyria and a band of gray matter calcification (a ‘‘pseudo-TORCH’’ syndrome).
Intragenic deletions and mutations were found in the gene encoding for occludin (OCLN) in patients from families with BLC-PMG.
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occludin mutations
- cataract
- multifocal haemorrhage and cystic destruction, predominantly in cerebral white matter and basal ganglia
- hydrocephalus ex vacuo; porencephalic cavitation
- subependymal calcification (CT)
JAM3 mutations
Pseudo-Torch syndrome can present due to JAM3 mutation (Mochida et al. 2010, Akawi et al. 2013, Kozak et al. 2024). JAM3 is essential for integrity of the cerebrovascular endothelium as well as for normal lens development. The tight junction, or zonula occludens, regulates epithelial permeability and it is a component of the blood-brain barrier. In addition tight junctions are involved in signal transduction. A homozygous mutation was reported in the tight-junction protein gene JAM3 in a large consanguineous family. Some members of this family had severe haemorrhagic destruction of the brain, subependymal calcification and congenital cataracts. This clinical presentation belongs with “pseudo-TORCH syndrome” as do mutations in occludin. Massive intracranial haemorrhage distinguishes JAM3 patients from others. Homozygosity mapping identified the disease locus on chromosome 11q25 with a maximum multipoint LOD score of 6.15. Sequence analysis of genes in the candidate interval uncovered a mutation in the canonical splice-donor site of intron 5 of JAM3.
- entry into the rest of the brain is prevented by tight junctions between astroglial cells (GC)
- away from the tanycyte layer, ependymal cells lining the ventricles are linked by gap junctions that allow free exchange between the CSF and brain interstitial fluid
- B: the blood–CSF barrier is situated in choroid plexus; barrier-forming cells are the epithelial cells CPE, with tight junctions at their apical side (CSF facing, arrowheads)
- blood vessels (BV) are fenestrated and do not form a barrier; apical microvilli increase exchange surface of epithelial cells to the i-CSF
- F: - blood vessels (BV) in the SAS have tight junctions with similar characteristics as cerebral blood
vessels (but without surrounding pericytes and astrocytic end-feet)
- blood vessels within the dura mater are fenestrated (f-BV)
- meningeal barrier:
arachnoid barrier cells ABC have tight junctions tj forming a barrier between the o-CSF in the
subarachnoid space SAS and superficial dural layers (dural border cells DBC and dura mater)
Abbott et al. 2006
- A: astroglial end feet encircle blood vessels during the first 2–3 weeks of postnatal development in rodents; these cellular structures are known collectively as the neurovascular unit
- C: circumventricular organ (median eminence, pineal gland, area postrema, subfornical organ) vessels have permeability similar to elsewhere in the body, allowing penetration of peptide hormones controlled by the hypothalamic–pituitary axis (prevented from entering the CSF by tanycytes TC with tight junctions tj between their apices)
- D: in adult brain ependymal cells are linked by gap junctions that do not restrict exchange of large molecules, such as proteins, between CSF and interstitial space
- E: in early brain development, strap junctions (arrowheads) are present between neuroepithelial cells (NE); these form a barrier restricting the movement of larger molecules, such as proteins, but not smaller molecules
bood brain barriers
Juctional proteins:
- VE-cadherin is a component of adherens junctions, but the subcellular localization of tight junctions and adherens junctions are almost same in brain endothelial cells
-these proteins interact with ZO-1/-2, which are oligomerized by themselves
- paracingulin is a recruiter of guanidine exchange factors (GEFs) to junctional areas and GEFs are necessary to activate small GTPases Rac1 or RhoA
- Rac1 strengthens the tight junctions while RhoA destabilizes the tight junctions and they inhibit each other
The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions and solutes (Hashimoto et al. 2023). The expression of CLDN-5 is tightly regulated in the BBB by other junctional proteins in endothelial cells and by supports from pericytes and astrocytes. The functional consequences are knwon of a recently identified pathogenic CLDN-5 missense mutation in patients with alternating hemiplegia of childhood. AHC is a severe disorder with infantile onset (before 1.5 years of age) recurrent episodes of hemiplegia on either side of the body with episodes alternating from one side to the other. Another known condition to cause AHC is mutation into ATP1A3, Na+-K+-ATPase pump (affecting 70–80% of patients with AHC).
Mutations into some other genes for ion transport, ATP1A2 (Na+-K+-ATPase pump), SCN1A (voltage-gated Na+ channel), and CACNA1A (voltage-gated Ca2+ channel) are known to cause sporadic or familial hemiplegic migraine (HM) with symptoms very similar to AHC but with an age of onset of 2–15 years.
All these mutations change excitability of neurons. Ion transport by the BBB is mainly transcellular, not paracellular because CLDN-5 forms a high electrical resistance barrier. Due to these ion transporters, the
cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) have a higher Na+ and Cl− concentration, a lower K+, Ca2+ concentration and equivalent HCO3− concentration compared to plasma. An anion permeable BBB may efflux transported Cl− and HCO3− to blood via the paracellular route and disturb ion homeostasis.
claudin5 mutations
the BBBarrier
JAM3 mutations
ESAM mutations
occludin mutations
claudin 5 mutations
disorders of cell tight junction molecules
Mutations of endothelial cell junctions that present in utero, with brain destruction, comprise:
- occludin
- Junctional Adhesion Molecule 3 (JAM3)
- endothelial cell adhesion molecule ESAM
Later presentation:
- JAM2: primary familial brain calcification (Cen et al. 2020)
- claudin 5: alternating hemiplegia in young children (Hashimoto et al. 2023)
An elaborate network of tight junctions (TJ) between endothelial cells is the structural basis of the BBB to restrict the paracellular diffusion of hydrophilic molecules [Engelhardt 2003, Brady and Siegel 2012, Saunders et al. 2018]. On top of that, the absence of fenestrae and the low pinocytotic activity of endothelial cells inhibit the transcellular passage of molecules across the barrier. For example, tight junctions, also termed zonae occludens, are constructed of the integral membrane protein occludin, which binds the linking proteins ZO-1 and ZO-2. These linking proteins are members of a large family, termed membrane-associated guanylyl kinase homologs (MAGUKs).
To meet the metabolic needs of the brain, specific transport systems, selectively expressed in the membranes of endothelial cells, mediate passage of nutrients (glucose, amino acids) and ions in or of toxic metabolites out of the CNS. Development of these systems is a progression from simple to complex tight junctions between endothelial cells (Steed et al. 2010) and requires interactions with pericytes, coordinated by growth factors like PDGF-B. Additionally, cadherin-mediated interactions between vessels play a role in stabilisation of this barrier, supporting its unique function in protecting the central nervous system.
Tracer stdues in day 5 wistar rats (Andersson et al. 2021) showed that experimental GMH (germinal matrix haemorrhage) produces a defined (and also rather distant) region surrounding the GMH where many vessels lose their integrity. This region expands for at least 6 h, thereafter the BBB is re-established within 5 days.
Biallelic loss of function variants in ESAM (endothelial cell adhesion molecule) can present with prenatal intracranial hemorrhage (Abdel-Salam et al. 2025), variable onset encephalopathy and seizures. Brain imaging in the neonatal period or early infancy showed variable onset intracranial hemorrhage that evolved to hydrocephalus in some, and hemosiderin deposits and porencephalic cysts were noted in one patient. Exome sequencing identified homozygous ESAM variants.
ESAM mutations
top left: at 2 weeks multiple porencephalic cysts and severe ventriculomegaly
bottom left: at 3 months mild ventriculomegaly, right porencephalic cyst, intracranial calcification, and areas of encephalomalacia
top right: at 4 months atrophy, ventriculomegaly, cavum septum pellucidum, porencephalic cysts, hemosiderin along the ependymal surfaces, mild cerebellar atrophy
bottom right: at 3 weeks showing multifocal intraparenchymal haemorrhages, and diffusely
hypodense brain parenchyma
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