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  • Open Access

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

Authors

  • Nadia A. Akawi,

    1. Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
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  • Fuat E. Canpolat,

    1. Zekai Tahir Burak Maternity Hospital, Neonatal Intensive Care Unit, Ankara, Turkey
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  • Susan M. White,

    1. Victorian Clinical Genetics Service, Murdoch Childrens Research Institute, Royal Children's Hospital, Australia
    2. Department of Paediatrics, University of Melbourne, Australia
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  • Josep Quilis-Esquerra,

    1. Molecular Genetics Unit. Consorci Sanitari de Terrassa, Terrassa, Barcelona, Spain
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  • Martin Morales Sanchez,

    1. Molecular Genetics Unit. Consorci Sanitari de Terrassa, Terrassa, Barcelona, Spain
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  • Maria José Gamundi,

    1. Molecular Genetics Unit. Consorci Sanitari de Terrassa, Terrassa, Barcelona, Spain
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  • Ganeshwaran H. Mochida,

    1. Division of Genetics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
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  • Christopher A. Walsh,

    1. Division of Genetics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
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  • Bassam R. Ali,

    Corresponding author
    • Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
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  • Lihadh Al-Gazali

    Corresponding author
    1. Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
    • Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
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  • Communicated by Segolène Ayme

  • Contract grant sponsors: Dubai Harvard Foundation for Medical Research (DHFMR) (2008-04); United Arab Emirates PhD scholarships programme, National Institutes of Health (NINDS) (RO1 NS035129).

Correspondence to: Lihadh Al-Gazali, Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates. E-mail: l.algazali@uaeu.ac.ae or Bassam R. Ali, Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates. E-Mail: bassam.ali@uaeu.ac.ae, br_ali@hotmail.com

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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