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Cited by 47Barrier Structure and Function StudiesGenomics and Rare DiseasesCell Adhesion Molecules Research

Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM 3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

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Akawi, Nadia A., Canpolat, Fuat E., White, Susan M., Quilis‐Esquerra, Josep, Morales Sanchez, Martin, Gamundi, Maria José, Mochida, Ganeshwaran H., Walsh, Christopher A. +2 more·2013·Human Mutation
DOI 10.1002/humu.22263PMC PMC3951164
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Abstract

We have recently shown that the hemorrhagic destruction of the brain, subependymal, calcification, and congenital cataracts is caused by biallelic mutations in the gene encoding junctional adhesion molecule 3 (JAM3) protein. Affected members from three new families underwent detailed clinical examination including imaging of the brain. Affected individuals presented with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. All patients had a catastrophic clinical course resulting in death. Sequencing the coding exons of JAM3 revealed three novel homozygous mutations: c.2T>G (p.M1R), c.346G>A (p.E116K), and c.656G>A (p.C219Y). The p.M1R mutation affects the start codon and therefore is predicted to impair protein synthesis. Cellular studies showed that the p.C219Y mutation resulted in a significant retention of the mutated protein in the endoplasmic reticulum, suggesting a trafficking defect. The p.E116K mutant traffics normally to the plasma membrane as the wild-type and may have lost its function due to the lack of interaction with an interacting partner. Our data further support the importance of JAM3 in the development and function of the vascular system and the brain.

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  • Homozygous mutations in the JAM-3 gene in humans encoding endothelial junctional molecule JAM-C result in a compromised blood-brain barrier, often brain hemorrhages, subependymal calcification, seizures, and congenital cataracts.

    “Homozygous mutations in JAM-3 gene in humans encoding endothelial junctional molecule JAM-C also result in a compromised BBB, often brain hemorrhages, subependymal calcification, seizures, and congenital cataracts (7).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [7]

    The Results (Mutation analysis) identify homozygous JAM3 mutations, and the Discussion (Clinical consequences of JAM3 deficiency) describes brain hemorrhage, subependymal calcification, congenital cataracts, and seizures in some affected children. The Introduction identifies JAM3 as JAM-C and discusses its role in junctions and permeability, but the paper does not establish that these mutations compromise the blood-brain barrier specifically. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Research works printed but not linked: 39

  1. 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 146A 2929 2936 18925673
  2. Al-Gazali LI Sztriha L Dawodu A Varady E Bakir M Khdir A Johansen J 1999 Complex consanguinity associated with short rib-polydactyly syndrome III and congenital infection-like syndrome: a diagnostic problem in dysmorphic syndromes J Med Genet 36 461 466 10874634 PMC1734389
  3. Ali BR Ben-Rebeh I John A Akawi NA Milhem RM Al-Shehhi NA Al-Ameri MM Al-Shamisi SA Al-Gazali L 2011 Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia PLoS One 6 e26206 22022569 PMC3194820
  4. Aridor M 2007 Visiting the ER: the endoplasmic reticulum as a target for therapeutics in traffic related diseases Adv Drug Deliv Rev 59 759 781 17681635
  5. Arrate MP Rodriguez JM Tran TT Brock TA Cunningham SA 2001 Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor J Biol Chem 276 45826 45832 11590146
  6. Balda MS Matter K 2008 Tight junctions at a glance J Cell Sci 121 3677 3682 18987354
  7. Bazzoni G Martinez-Estrada OM Orsenigo F Cordenonsi M Citi S Dejana E 2000 Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin J Biol Chem 275 20520 20526 10877843
  8. Betanzos A Schnoor M Severson EA Liang TW Parkos CA 2009 Evidence for cross-reactivity of JAM-C antibodies: implications for cellular localization studies Biol Cell 101 441 453 19143587 PMC2877264
  9. Bradfield PF Nourshargh S Aurrand-Lions M Imhof BA 2007 JAM family and related proteins in leukocyte migration (Vestweber series) Arterioscler Thromb Vasc Biol 27 2104 2112 17615384
  10. Burdon KP McKay JD Sale MM Russell-Eggitt IM Mackey DA Wirth MG Elder JE Nicoll A Clarke MP FitzGerald LM 2003 Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation Am J Hum Genet 73 1120 1130 14564667 PMC1180491
  11. Carlton VE Harris BZ Puffenberger EG Batta AK Knisely AS Robinson DL Strauss KA Shneider BL Lim WA Salen G 2003 Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT Nat Genet 34 91 96 12704386
  12. Cereijido M Contreras RG Shoshani L Flores-Benitez D Larre I 2008 Tight junction and polarity interaction in the transporting epithelial phenotype Biochim Biophys Acta 1778 770 793 18028872
  13. Chen Y Bellamy WP Seabra MC Field MC Ali BR 2005 ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome Hum Mol Genet 4 2559 2569 16049033
  14. Colom B Poitelon Y Huang W Woodfin A Averill S Del Carro U Zambroni D Brain SD Perretti M Ahluwalia A Priestley JV Chavakis T 2012 Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves FASEB J 26 1064 1076 22090315 PMC3370675
  15. Daniele LL Adams RH Durante DE Pugh EN Jr Philp NJ 2007 Novel distribution of junctional adhesion molecule-C in the neural retina and retinal pigment epithelium J Comp Neurol 505 166 176 17853450 PMC3144860
  16. de Vries LS Koopman C Groenendaal F Van Schooneveld M Verheijen FW Verbeek E Witkamp TD van der Worp HB Mancini G 2009 COL4A1 mutation in two preterm siblings with antenatal onset of parenchymalhemorrhage Ann Neurol 65 12 18 19194877
  17. Ebnet K 2008 Organization of multiprotein complexes at cell-cell junctions Histochem Cell Biol 130 1 20 18365233 PMC2413109
  18. Ebnet K Suzuki A Ohno S Vestweber D 2004 Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117 19 29 14657270
  19. Fowler M Dow R White TA Greer CH 1972 Congenital hydrocephalus-hydrencephaly in five siblings, with autopsy studies: a new disease Dev Med Child Neurol 14 173 88 4555262
  20. Fukuda Y Aguilar-Bryan L Vaxillaire M Dechaume A Wang Y Dean M Moitra K Bryan J Schuetz JD 2011 Conserved intramolecular disulfide bond is critical to trafficking and fate of ATP-binding cassette (ABC) transporters ABCB6 and sulfonylurea receptor 1 (SUR1)/ABCC8 J Biol Chem 286 8481 92 21199866 PMC3048732
  21. Gliki G Ebnet K Aurrand-Lions M Imhof BA Adams RH 2004 Spermatid differentiation requires the assembly of a cell polarity complex downstream of junctional adhesion molecule-C Nature 431 320 324 15372036
  22. Gould DB Phalan FC van Mil SE Sundberg JP Vahedi K Massin P Bousser MG Heutink P Miner JH Tournier-Lasserve E John SW 2006 Role of COL4A1 in small-vessel disease and hemorrhagic stroke N Engl J Med 354 1489 1496 16598045
  23. Konrad M Schaller A Seelow D Pandey AV Waldegger S Lesslauer A Vitzthum H Suzuki Y Luk JM Becker C Schlingmann KP Schmid M 2006 Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement Am J Hum Genet 79 949 957 17033971 PMC1698561
  24. Lalonde E Albrecht S Ha KC Jacob K Bolduc N Polychronakos C Dechelotte P Majewski J Jabado N 2010 Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing Hum Mutat 31 918 923 20518025
  25. Matter K Balda MS 2007 Tight junctions, gene expression and nucleo-junctinal interplay J Cell Sci 120 1505 1511 17452622
  26. Meyer E Ricketts C Morgan NV Morris MR Pasha S Tee LJ Rahman F Bazin A Bessières B Déchelotte P Yacoubi MT Al-Adnani 2010 Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome) Am J Hum Genet 86 471 478 20206334 PMC2833392
  27. 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 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 87 882 889 21109224 PMC2997371
  28. Plaisier E Gribouval O Alamowitch S Mougenot B Prost C Verpont MC Marro B Desmettre T Cohen SY Roullet E Dracon M Fardeau M 2007 COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps N Engl J Med 357 2687 2695 18160688
  29. Rudarakanchana N Flanagan JA Chen H Upton PD Machado R Patel D Trembath RC Morrell NW 2002 Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension Hum Mol Genet 11 1517 1525 12045205
  30. Santoso S Sachs UJH Kroll H Linder M Ruf A Preissner KT Chavakis T 2002 The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1 J Exp Med 196 679 691 12208882 PMC2194005
  31. Scheiermann C Meda P Aurrand-Lions M Madani R Yiangou Y Coffey P Salt TE Ducrest-Gay D Caille D Howell O Reynolds R Lobrinus A 2007 Expression and function of junctional adhesion molecule-C in myelinated peripheral nerves Science 318 1472 1475 18048693 PMC3299566
  32. Sibon I Coupry I Menegon P Bouchet JP Gorry P Burgelin I Calvas P Orignac I Dousset V Lacombe D Orgogozo JM Arveiler B 2007 COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke Ann Neurol 62 177 184 17696175
  33. Simon DB Lu Y Choate KA Velazquez H Al-Sabban E Praga M Casari G Bettinelli A Colussi G Rodriguez-Soriano J McCredie D Milford D 1999 Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption Science 285 103 106 10390358
  34. Steed E Balda MS Matter K 2010 Dynamics and functions of tight junctions Trends Cell Biol 20 142 149 20061152
  35. Stelzer S Worlitzer MM Bahnassawy L Hemmer K Rugani K Werthschulte I Schön AL Brinkmann BF Bunk EC Palm T Ebnet K Schwamborn JC 2012 JAM-C is an apical surface marker for neural stem cells Stem Cells Dev 21 757 66 22114908
  36. Teichmann SA Chothia C 2000 Immunoglobulin superfamily proteins in Caenorhabditis elegans J Mol Biol 296 1367 1383 10698639
  37. Terry S Nie M Matter K Balda MS 2010 Rho signaling and tight junction functions Physiology (Bethesda) 25 16 26 20134025
  38. Weber C Fraemohs L Dejana E 2007 The role of junctional adhesion molecules in vascular inflammation Nat Rev Immunol 7 467 477 17525755
  39. Wilcox ER Burton QL Naz S Riazuddin S Smith TN Ploplis B Belyantseva I Ben-Yosef T Liburd NA Morell RJ 2001 Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29 Cell 104 165 172 11163249

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Authors
Akawi, N. A., Canpolat, F. E., White, S. M., Quilis‐Esquerra, J., Morales Sanchez, M., Gamundi, M. J., Mochida, G. H., Walsh, C. A., Ali, B. R., & Al‐Gazali, L.
Affiliations
  • United Arab Emirates University (AE)
  • Zekai Tahir Burak Maternity Hospital, Neonatal Intensive Care Unit Ankara Turkey
  • Royal Children's Hospital (AU)
  • Consorci Sanitari de Terrassa (ES)
  • Molecular Genetics Unit. Consorci Sanitari de Terrassa Terrassa Barcelona Spain
  • Boston Children's Hospital (US)
Corresponding author
  • Ali, Bassam R.
  • Al‐Gazali, Lihadh
ORCID
Venue
Human Mutation
Publisher
Hindawi Limited
Published
2013-03
Volume
34
Issue
3
Pages
498-505
ISSN
  • 1059-7794 (ISSN-L)
  • 1098-1004
DOI
10.1002/humu.22263
PMC
PMC3951164
OpenAlex
W2059904798
Cited by
47
References
3
Citations by year
2026: 2 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 2
FWCI
0.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • Dubai Harvard Foundation for Medical Research
  • Fondation pour la Recherche Médicale
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS035129, R01NS035129, R37NS035129)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
JAM3, subependymal calcification, congenital cataract, novel homozygous mutation, endoplasmic reticulum retention, plasma membrane trafficking, vascular development, brain development, genotype-phenotype correlation
MeSH terms
Australia, Brain, Calcinosis, Cataract, Cerebral Hemorrhage, Exons, Female, HeLa Cells, Homozygote, Humans, Infant, Newborn, Intensive Care Units, Neonatal, Male, Pedigree, Phenotype, Spain, Turkey, United Arab Emirates, Cell Adhesion Molecules, Sequence Analysis, DNA, Microscopy, Confocal, Mutation, Missense

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