OTX2 mutations contribute to the otocephaly-dysgnathia complex
OTX2 mutations contribute to the otocephaly-dysgnathia complex
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DOI：
10.1136/jmedgenet-2012-100892
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发表时间：
2012-06-01
影响因子：
4
通讯作者：
Jabs, Ethylin Wang
中科院分区：
文献类型：
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作者：
Chassaing, Nicolas;Sorrentino, Susanna;Jabs, Ethylin Wang
背景耳头畸形或dysgnathia复杂的特点是下颌发育不全/发育不全，耳异常，小口，和microglossia;这种发育缺陷的分子基础在很大程度上是未知的humans.Methods和结果本研究报告了一个大的家庭中，两个堂兄弟与微/anophthalmia每个生了至少一个孩子与耳头畸形，这表明无眼症和耳头畸形之间的遗传关系。在该家族中筛查了已知的小眼畸形基因座OTX 2，发现了移码突变。该研究随后在一名无关的耳头患者中发现了散发性OTX 2突变。由于OTX 2突变可能不足以引起耳头畸形，因此该研究在已知耳头畸形基因抑制的背景下测定了otx 2改变颅面表型的潜力。研究发现，otx 2可以与pgap 1、prrx 1和msx 1发生遗传相互作用，加剧斑马鱼发育过程中下颌骨和中线的缺陷。然而，这些位点的OTX 2阳性家族的测序没有发现可能的致病性病变，进一步表明遗传异质性和complication.Conclusion鉴定OTX 2参与耳头畸形/dysgnathia在人类，即使在这个位点的功能突变的损失不足以解释这些患者的复杂的解剖缺陷，表明需要第二次遗传命中。与这一观点相一致，otx 2和其他发育相关基因的反式抑制重现了斑马鱼耳头畸形表型的各个方面。这项研究强调了遗传学和功能方法的结合效用，以解剖支配颅面发育的调控途径和这一疾病组的遗传学。
Background Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans.Methods and results This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2, a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1, prrx1, and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity.Conclusion Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.