Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene
Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene
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DOI：
10.1002/ajmg.a.32242
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发表时间：
2008-04-15
影响因子：
2
通讯作者：
Kraus, Cornelia
中科院分区：
文献类型：
--
作者：
Graul-Neumann, Luitgard M.;Hausser, Ingrid;Kraus, Cornelia
常染色体显性先天性皮肤松弛症 (ADCL) 具有遗传异质性，并表现出临床变异性。之前仅描述了 7 个具有弹性蛋白基因 (ELN) 突变的 ADCL 家族。我们对皮肤松弛症亲属进行了形态学和分子遗传学研究，该皮肤松弛症亲属具有先前未描述的由新型 ELN 突变 c 引起的高度可变的表型。 1621 C > T。先证者出现严重的皮肤松弛、严重的先天性肺部疾病（以前在 ADCL 中未描述过）和肺动脉疾病（在 ARCL 中常见，但在 ADCL 中罕见）。他还患有婴儿痉挛症（OMIM 308350；韦斯特综合征），我们认为这是巧合的关联，尽管不能排除隐性皮肤松弛甚至双基因遗传。先证者真皮的电子显微镜仅显示弹性纤维轻度稀疏（与大多数隐性皮肤松弛类型相反）。除了轻度弹力纤维断裂外，先证者父亲的皮肤形态均在正常范围内。使用血液中的基因组 DNA 和培养的皮肤成纤维细胞的 RNA 对 ELN 基因进行分子分析，表明先证者及其临床健康的父亲存在新的剪接位点突变。对成纤维细胞中 ELN 表达的分析为孩子的显性负效应提供了证据，而由于未知的机制，父亲表现出单倍体不足，这可能解释了显着的临床变异。 (C) 2008 Wiley-Liss, Inc.
Autosomal dominant congenital cutis laxa (ADCL) is genetically heterogeneous and shows clinical variability. Only seven ADCL families with mutations in the elastin gene (ELN) have been described previously. We present morphological and molecular genetic studies in a cutis laxa kindred with a previously undescribed highly variable phenotype caused by a novel ELN mutation c. 1621 C > T. The proband presented with severe cutis laxa, severe congenital lung disease previously undescribed in ADCL and pulmonary artery disease, which is often seen in ARCL but rare in ADCL. He also developed infantile spasms (OMIM 308350; West syndrome), which we consider a coincidental association although recessive cutis laxa or even digenic inheritance cannot be excluded. Electron microscopy of the proband's dermis revealed only mild rarefication of elastic fibers (in contrast to most recessive cutis laxa types). Apart from mild elastic fiber fragmentation, dermal morphology of the proband's father was within normal range. Molecular analysis of the ELN gene using genomic DNA from blood and RNA from cultured skin fibroblasts indicated a novel splice site mutation in the proband and his clinically healthy father. Analysis of ELN expression in fibroblasts provided evidence for a dominant-negative effect in the child, while due to an unknown mechanism, the father showed haploinsufficiency which might explain the significant clinical variability. (C) 2008 Wiley-Liss, Inc.