Communicated by Segolène Ayme
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
Article first published online: 18 FEB 2013
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 3, pages 498–505, March 2013
How to Cite
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. and 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: 498–505. doi: 10.1002/humu.22263
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).
- Issue published online: 18 FEB 2013
- Article first published online: 18 FEB 2013
- Accepted manuscript online: 15 DEC 2012 10:19PM EST
- Manuscript Accepted: 5 DEC 2012
- Manuscript Received: 27 JUN 2012
- Dubai Harvard Foundation for Medical Research (DHFMR). Grant Number: 2008-04
- United Arab Emirates PhD scholarships programme, National Institutes of Health (NINDS). Grant Number: RO1 NS035129
- subependymal calcification;
- congenital cataract;
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.