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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
Author(s) -
Akawi Nadia A.,
Canpolat Fuat E.,
White Susan M.,
QuilisEsquerra Josep,
Morales Sanchez Martin,
Gamundi Maria José,
Mochida Ganeshwaran H.,
Walsh Christopher A.,
Ali Bassam R.,
AlGazali Lihadh
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22263
Subject(s) - biology , subependymal zone , calcification , mutation , mutant , exon , phenotype , genetics , frameshift mutation , gene , pathology , microbiology and biotechnology , anatomy , medicine
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 ( JAM 3) 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 JAM 3 revealed three novel homozygous mutations: c.2 T > G (p. M 1 R ), c.346 G > A (p. E 116 K ), and c.656 G > A (p. C 219 Y ). The p. M 1 R mutation affects the start codon and therefore is predicted to impair protein synthesis. Cellular studies showed that the p. C 219 Y mutation resulted in a significant retention of the mutated protein in the endoplasmic reticulum, suggesting a trafficking defect. The p. E 116 K 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 JAM 3 in the development and function of the vascular system and the brain.