A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

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A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts Ganeshwaran H. Mochida, Vijay S. Ganesh, Jillian M. Felie, Danielle Gleason, R. Sean Hill, Katie Rose Clapham, Daniel Rakiec, Wen- Hann Tan, Nadia Akawi, Muna Al-Saffar, Jennifer N. Partlow, Sigrid Tinschert, A. James Barkovich, Bassam Ali, Lihadh Al-Gazali, Christopher A. Walsh The American Journal of Human Genetics Volume 87, Issue 6, Pages 882-889 (December 2010) DOI: 10.1016/j.ajhg.2010.10.026 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree Drawing of the Family OTH10700 Filled symbols denote affected individuals. The left half of the symbol is filled for the syndrome of hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts, and the right half of the symbol is filled for short rib-polydactyly syndrome, type III. Genotyped individuals are indicated with an asterisk. The American Journal of Human Genetics 2010 87, 882-889DOI: (10.1016/j.ajhg.2010.10.026) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain Imaging of the Family OTH10700 A T1-weighted axial brain MRI (A) and brain CT (B) of individual VIII-21, a brain CT of individual VIII-22 (C), and a T1-weighted sagittal brain MRI of individual VIII-10 (D) show multifocal intraparenchymal hemorrhage, predominantly in the cerebral white matter and basal ganglia (arrows). A T2-weighted axial brain MRI of individual VIII-27 (E) shows massive cystic destruction of the cerebral white matter and basal ganglia and resulting large lateral ventricles. A brain CT of individual VIII-29 (F) shows a porencephalic cyst centered in the left frontal subcortical white matter (asterisk), enlarged lateral ventricles, and reduced white-matter volume, indicative of destructive changes. Subependymal calcification is evident on CT (B, C and F, arrowheads). Figure 2A is from the same MRI series previously published in Al-Gazali et al.7 (this individual is referred to as case 4 in the paper). The American Journal of Human Genetics 2010 87, 882-889DOI: (10.1016/j.ajhg.2010.10.026) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Homozygosity Mapping and Linkage Analysis of the Family OTH10700 (A) SNP genotyping results on chromosome 11q25. A block of homozygosity shared only by the affected individuals tested (VIII-21, VIII-22, VIII-10, and VIII-29) is evident and delineated by the vertical lines. Red and blue indicate homozygous SNP markers, and green indicates heterozygous SNP markers. (B) LOD score graph of the candidate region. A maximum multipoint LOD score of 6.15 was obtained within the candidate interval. (C) Genes within the candidate region, shown as the RefSeq track of the UCSC Genome Browser (NCBI build 36/hg18). The American Journal of Human Genetics 2010 87, 882-889DOI: (10.1016/j.ajhg.2010.10.026) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutation in JAM3 (A) Genomic DNA analysis of JAM3. Affected individual VIII-29 shows a G-to-T change in the canonical splice donor site of JAM3 intron 5 (c.747+1G>T; asterisk). Her mother (VII-5) is heterozygous for the mutation. A cryptic splice donor site 19 bp downstream is at least equally as potent as the wild-type donor site (confidence score 0.46 [wild-type] versus 0.67 [cryptic] by NetGene2). CTRL = normal control. (B) mRNA analysis of JAM3. On the mRNA level, the mutation results in the usage of the downstream cryptic splice donor site and causes a 19 bp insertion in the affected individual (VIII-29). Only normal splice products are seen in her mother (VII-5). (C) Predicted protein product of the mutant allele. The 19 bp insertion is expected to result in a truncating protein product with 25 aberrant amino acid residues in the C terminus (WT = wild-type protein, MUT = mutant protein). The truncation occurs proximal to the transmembrane domain (TM) and PDZ-binding motif (+). The American Journal of Human Genetics 2010 87, 882-889DOI: (10.1016/j.ajhg.2010.10.026) Copyright © 2010 The American Society of Human Genetics Terms and Conditions