A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts
A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts
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DOI：
10.1016/j.ajhg.2010.10.026
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发表时间：
2010-12-10
影响因子：
9.8
通讯作者：
Walsh, Christopher A.
中科院分区：
文献类型：
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作者：
Mochida, Ganeshwaran H.;Ganesh, Vijay S.;Walsh, Christopher A.
紧密连接或闭合小带是一种特殊的细胞-细胞连接，调节上皮和内皮的通透性，是脑血管内皮中血脑屏障的重要组成部分。除了作为扩散屏障，紧密连接还参与信号转导。在这项研究中，我们确定了紧密连接蛋白基因JAM 3的纯合突变在一个大的血缘家庭从阿拉伯联合酋长国。这个家族的一些成员患有罕见的常染色体隐性遗传综合征，其特征是严重的脑出血性破坏、室管膜下钙化和先天性白内障。他们的临床表现与一些报道的假TORCH综合征病例以及涉及紧密连接复合体的另一种成分occludin突变的病例重叠。然而，大量颅内出血使这些患者与其他患者不同。纯合性定位确定了该家系中染色体11 q25上的疾病位点，最大多点LOD评分为6.15。在候选区间的基因序列分析发现一个突变的典型剪接供体位点的内含子5的JAM 3。患者淋巴母细胞系的RT-PCR分析证实了异常剪接，导致移码突变和早期终止。已知JAM 3存在于血管内皮中，尽管其在脑血管系统中的作用尚未被涉及。我们的研究结果表明，JAM 3是必不可少的维持脑血管内皮细胞的完整性，以及正常的透镜的发展在人类。
The tight junction, or zonula occludens, is a specialized cell-cell junction that regulates epithelial and endothelial permeability, and it is an essential component of the blood-brain barrier in the cerebrovascular endothelium. In addition to functioning as a diffusion barrier, tight junctions are also involved in signal transduction. In this study, we identified a homozygous mutation in the tight-junction protein gene JAM3 in a large consanguineous family from the United Arab Emirates. Some members of this family had a rare autosomal-recessive syndrome characterized by severe hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Their clinical presentation overlaps with some reported cases of pseudo-TORCH syndrome as well as with cases involving mutations in occludin, another component of the tight-junction complex. However, massive intracranial hemorrhage distinguishes these patients from others. Homozygosity mapping identified the disease locus in this family on chromosome 11q25 with a maximum multipoint LOD score of 6.15. Sequence analysis of genes in the candidate interval uncovered a mutation in the canonical splice-donor site of intron 5 of JAM3. RT-PCR analysis of a patient lymphoblast cell line confirmed abnormal splicing, leading to a frameshift mutation with early termination. JAM3 is known to be present in vascular endothelium, although its roles in cerebral vasculature have not been implicated. Our results suggest that JAM3 is essential for maintaining the integrity of the cerebrovascular endothelium as well as for normal lens development in humans.