Asymmetric Lower-Limb Malformations in Individuals with Homeobox PITX1 Gene Mutation
Asymmetric Lower-Limb Malformations in Individuals with Homeobox PITX1 Gene Mutation
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DOI：
10.1016/j.ajhg.2008.10.004
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发表时间：
2008-11-07
影响因子：
9.8
通讯作者：
Dobbs, Matthew B.
中科院分区：
文献类型：
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作者：
Gurnett, Christina A.;Alaee, Farhang;Dobbs, Matthew B.
马蹄内翻足是最常见的严重肌肉骨骼出生缺陷之一，全球发病率为1/1000活产婴儿。在本研究中，我们描述了一个五代家庭与不对称的右侧为主的特发性马蹄内翻足分离作为一个常染色体显性条件与不完全的遗传。其他下肢畸形，包括髌骨发育不全，斜距，胫骨半肢畸形，发育性髋关节发育不良和轴前多指畸形，也存在于一些家庭成员。全基因组连锁分析与Affyssin基因芯片作图10K定位数据从这个家庭的13个成员揭示了一个多点的LODmax为3.31染色体5q31。PITX1是一种对后肢发育至关重要的bicoid相关同源域转录因子，在该家族中发现了一个单错义突变（c.388G-> A），并与疾病分离。PITX1 E130K突变位于高度保守的同源结构域，并降低了PITX1反式激活荧光素酶报告基因的能力。PITX 1 E130 K突变也以剂量依赖性方式抑制野生型PITX I活性，表明对转录的显性负效应。胫骨半肢畸形和马蹄内翻足右侧受累的倾向表明PITX1或涉及PITX1的通路可能参与其病因。在马蹄内翻足发病机制中，一个参与早期肢体发育的基因的意义也为人类特发性马蹄内翻足病因学的未来研究提供了额外的途径。
Clubfoot is one of the most common severe musculoskeletal birth defects, with a worldwide incidence of 1 in 1000 live births. In the present study, we describe a five-generation family with asymmetric right-sided predominant idiopathic clubfoot segregating as an autosomal-dominant condition with incomplete penetrance. Other lower-limb malformations, including patellar hypoplasia, oblique talus, tibial hemimelia, developmental hip dysplasia, and preaxial polydactyly, were also present in some family members. Genome-wide linkage analysis with Affymetrix GeneChip Mapping 10K mapping data from 13 members of this family revealed a multipoint LODmax of 3.31 on chromosome 5q31. A single missense mutation (c.388G -> A) was identified in PITX1, a bicoid-related homeodomain transcription factor critical for hindlimb development, and segregated with disease in this family. The PITX1 E130K mutation is located in the highly conserved homeodomain and reduces the ability of PITX1 to transactivate it luciferase reporter. The PITX1 E130K mutation also suppresses wild-type PITX I activity in a dose-dependent manner, Suggesting dominant-negative effects on transcription. The propensity for right-sided involvement in tibial hemimelia and clubfoot suggests that PITX1, or pathways involving PITX1, may be involved in their etiology. Implication of a gene involved in early limb development in clubfoot pathogenesis also Suggests additional pathways for future investigations of idiopathic Clubfoot etiology in humans.