Cella Wener, de Vasconcellos José Paulo Cabral, de Melo Mônica Barbosa, Kneipp Bianca, Costa Fernando Ferreira, Longui Carlos Alberto, Costa Vital Paulino
Department of Ophthalmology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
Invest Ophthalmol Vis Sci. 2006 May;47(5):1803-9. doi: 10.1167/iovs.05-0979.
Axenfeld-Rieger (AR) is an autosomal dominant disorder with phenotypic heterogeneity characterized by anterior segment dysgenesis, facial bone defects, and redundant periumbilical skin. The PITX2 gene, on chromosome 4q25, and the FOXC1 gene, on chromosome 6p25, have been implicated in the different phenotypes of the syndrome through mutational events. Recently, the CYP1B1 gene was found to be associated with Peters' anomaly, and the gene associated with oculodentodigital dysplasia syndrome, which presents some similarities with AR, was identified (connexin 43--GJA1 gene). The purpose of this study was to evaluate PITX2, FOXC1, CYP1B1, and GJA1 gene mutations in Brazilian families with AR.
Eight unrelated patients affected by AR (all eight with glaucoma and three with systemic manifestations) and their families were ophthalmologically evaluated and their blood was collected for DNA extraction purposes. The coding regions of PITX2, FOXC1, CYP1B1, and GJA1 genes were completely evaluated through direct sequencing.
The frequency of mutations in the FOXC1, GJA1, PITX2, and CYP1B1 genes in this study were 25%, 12.5%, 0% and 0%, respectively. In the FOXC1 gene, two GGC triplet insertions (GGC375ins and GGC447ins) defined as a polymorphism, and two new mutations--a deletion (718 to 719delCT) and a nonsense mutation (Trp152STOP)--were identified. One polymorphism (Ala253Val) was identified in the GJA1 gene in the same family presenting the Trp152STOP mutation in the FOXC1 gene. In this family harboring both structural alterations, two patients who carried the GJA1 (Ala253Val) and FOXC1 (Trp152STOP) mutations developed less severe glaucoma compared with family members presenting the FOXC1 (Trp152STOP) mutation alone.
Two new structural alterations in the FOXC1 gene and a polymorphism in the GJA1 gene were first described in Brazilian patients with AR and developmental glaucoma. A polymorphism in the GJA1 gene (Ala253Val), for the first time identified in association with AR, raises the possibility of its participation as a modifier gene.
Axenfeld-Rieger（AR）综合征是一种常染色体显性疾病，具有表型异质性，其特征为眼前节发育异常、面部骨骼缺陷和脐周皮肤冗余。位于4号染色体q25区域的PITX2基因和位于6号染色体p25区域的FOXC1基因，已被证实通过突变事件与该综合征的不同表型相关。最近，发现CYP1B1基因与彼得斯异常有关，并且鉴定出了与眼齿指发育异常综合征相关的基因，该综合征与AR有一些相似之处（连接蛋白43——GJA1基因）。本研究的目的是评估巴西AR综合征家系中PITX2、FOXC1、CYP1B1和GJA1基因的突变情况。
对8例患有AR综合征的非亲缘关系患者（8例均患有青光眼，3例有全身表现）及其家族进行眼科评估，并采集他们的血液用于DNA提取。通过直接测序对PITX2、FOXC1、CYP1B1和GJA1基因的编码区进行全面评估。
本研究中，FOXC1、GJA1、PITX2和CYP1B1基因的突变频率分别为25%、12.5%、0%和0%。在FOXC1基因中，鉴定出两个GGC三联体插入（GGC375ins和GGC447ins），定义为多态性，以及两个新的突变——一个缺失（718至719delCT）和一个无义突变（Trp152STOP）。在FOXC1基因发生Trp152STOP突变的同一家族中，GJA1基因鉴定出一个多态性（Ala253Val）。在这个同时存在两种结构改变的家族中，与仅携带FOXC1（Trp152STOP）突变的家族成员相比，两名携带GJA1（Ala253Val）和FOXC1（Trp152STOP）突变的患者青光眼病情较轻。
首次在患有AR综合征和发育性青光眼的巴西患者中描述了FOXC1基因的两种新结构改变以及GJA1基因的一个多态性。首次发现与AR综合征相关的GJA1基因多态性（Ala253Val），增加了其作为修饰基因参与其中的可能性。
