Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa
Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa
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DOI：
10.1002/ajmg.a.31980
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发表时间：
2007-11-15
影响因子：
2
通讯作者：
Chu, Mon-Li
中科院分区：
文献类型：
--
作者：
Dasouki, Majed;Markova, Dessislava;Chu, Mon-Li
涉及弹性组织蛋白的突变导致影响皮肤、骨骼、眼和血管结构（包括曲折的血管和皮肤拉克萨）的广谱表型。在这里，我们报告一个女性新生儿明显长手指，主动脉瘤，曲折的肺动脉和轻度全身皮肤松弛。她死于27天的年龄线索严重呼吸窘迫和不可手术的全身血管异常。皮肤活检显示弹性纤维明显缺乏和断裂，尸检显示肺动脉闭塞。DNA分析鉴定了fibulin-4（最近认识到的弹性纤维相关蛋白）中的复合杂合突变（（c.835C > T（p.R279C）/c.1070_1073dupCCGC）。对患者皮肤成纤维细胞的分析表明，从一个等位基因转录的具有4-bp重复的纤蛋白-4 mRNA可能受到无义介导的衰变，而来自另一个等位基因的错义R279 C纤蛋白-4蛋白的合成和分泌严重受损。免疫组化染色显示，在患者成纤维细胞沉积的细胞外基质中完全不存在fibulin-4纤维。我们的研究提供证据表明，缺乏fibulin-4导致围产期致命的条件与弹性组织异常。(C)2007 Wiley-Liss，Inc.
Mutations involving elastic tissue proteins result in a broad spectrum of phenotypes affecting skin, skeleton, ocular and vascular structures, including tortuous blood vessels and cutis laxa. Here we report on a female newborn with apparently long fingers, aortic aneurysm, tortuous pulmonary arteries and mild generalized lax skin. She died at 27 days of age clue to severe respiratory distress and inoperable systemic vascular abnormalities. Skin biopsy showed marked paucity and fragmentation of elastic fibers and autopsy revealed occlusion of the pulmonary artery. DNA analysis identified compound heterozygous mutations ((c.835C > T (p.R279C)/c.1070_1073dupCCGC) in fibulin-4, a recently recognized elastic fiber associated protein. Analyses of dermal fibroblasts from the patient indicated that fibulin-4 mRNAs with the 4-bp duplication transcribed from one allele are probably subject to,nonsense-mediated decay, whereas synthesis and secretion of the missense R279C fibulin-4 protein from the other allele is severely impaired. Immunostaining demonstrated a total absence of fibulin-4 fibers in the extracellular matrix deposited by the patient's fibroblasts. Our studies provide evidence that deficiency in fibulin-4 leads to a perinatal lethal condition associated with elastic tissue abnormalities. (C) 2007 Wiley-Liss, Inc.