PORCN Mutations in Focal Dermal Hypoplasia: Coping with Lethality
PORCN Mutations in Focal Dermal Hypoplasia: Coping with Lethality
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DOI：
10.1002/humu.20992
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发表时间：
2009-05-01
期刊：
影响因子：
3.9
通讯作者：
Grzeschik, Karl-Heinz
中科院分区：
文献类型：
--
作者：
Bornholdt, Dorothea;Oeffner, Frank;Grzeschik, Karl-Heinz
X连锁显性特征局灶性皮肤发育不全（FDH，Goltz综合征）是一种发育缺陷，由于来自活性X染色体上携带有害PORCN突变的细胞的Wnt信号传递受阻而导致受影响组织的局灶性分布。来自不同种族背景的24名无关患者的分子特征显示，Xp11.23中PORCN基因存在23种不同的突变。三个是微缺失，消除了PORCN，并包含了邻近的基因，如EBP，与Conradi-Hunermann-Happle综合征（CDPX 2）相关的基因。12/24例患者携带导致功能丧失的无义突变。在一种情况下，典型的剪接受体位点发生突变，8个错义突变交换了高度保守的氨基酸。FDH患者通过女性X染色体失活的极端偏斜来克服潜在致命的X染色体突变的后果，从而能够在家族中传递该性状，或者通过男性和女性个体中的合子后嵌合现象来克服潜在致命的X染色体突变的后果。在诊断为Goltz综合征的病例中，PORCN突变的分子表征与患者及其家属的遗传咨询特别相关，因为没有功能性诊断测试可用，并且由于与镶嵌状态相关的相当大的表型变异性，突变的携带者可能会被忽视。c 2009 Wiley-Liss，Inc.
The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status. c 2009 Wiley-Liss, Inc.