Passos-Bueno Maria Rita, Ornelas Camila C, Fanganiello Roberto D
Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, Brazil.
Am J Med Genet A. 2009 Aug;149A(8):1853-9. doi: 10.1002/ajmg.a.32950.
Our aim in this review is to discuss currently known mechanisms associated with three important syndromes of the first and second pharyngeal arches: Treacher Collins syndrome (TCS), Oculo-auriculo-vertebral syndrome (AOVS) and Auriculo-Condylar syndrome (ACS) or question mark ear syndrome. TCS and ACS are autosomal dominant diseases, with nearly complete penetrance and wide spectrum of clinical variability. The phenotype of the latter has several overlapping features with OAVS, but OAVS may exist in both sporadic and autosomal dominant forms. Mutations in the TCOF1 gene are predicted to cause premature termination codons, leading to haploinsuficiency of the protein treacle and causing TCS. Low amount of treacle leads ultimately to a reduction in the number of cranial neural crest cells migrating to the first and second pharyngeal arches. Other than TCS, the genes associated with ACS and OAVS are still unknown. The first locus for ACS was mapped by our group to 1p21-23 but there is genetic heretogeneity. Genetic heterogeneity is also present in OAVS. Based on the molecular analysis of balanced translocation in an OAVS patient, it has been suggested that abnormal expression of BAPX1 possibly due to epigenetic disregulation might be involved with the etiology of OAVS. Involvement of environmental events has also been linked to the causation of OAVS. Identification of factors leading to these disorders are important for a comprehensive delineation of the molecular pathways underlying the craniofacial development from the first and the second pharyngeal arches, for genetic counseling and to open alternative strategies for patient treatment.
在本综述中，我们的目的是讨论与第一和第二咽弓的三种重要综合征相关的已知机制：特雷彻·柯林斯综合征（TCS）、眼耳脊椎综合征（AOVS）和耳髁综合征（ACS）或问号耳综合征。TCS和ACS是常染色体显性疾病，具有几乎完全的外显率和广泛的临床变异性。后者的表型与OAVS有几个重叠特征，但OAVS可能以散发性和常染色体显性形式存在。预计TCOF1基因中的突变会导致过早终止密码子，导致treacle蛋白单倍体不足并引起TCS。treacle数量减少最终会导致迁移到第一和第二咽弓的颅神经嵴细胞数量减少。除了TCS，与ACS和OAVS相关的基因仍然未知。我们团队将ACS的第一个基因座定位到1p21 - 23，但存在遗传异质性。OAVS中也存在遗传异质性。基于对一名OAVS患者平衡易位的分子分析，有人提出BAPX1的异常表达可能由于表观遗传失调而与OAVS的病因有关。环境因素也与OAVS的病因有关。确定导致这些疾病的因素对于全面描述第一和第二咽弓颅面发育的分子途径、进行遗传咨询以及为患者治疗开辟替代策略很重要。
