Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics.
Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics.
复制标题
常染色体显性白内障和前节失调的比利时家族中的新型PITX3突变具有相似的表型和功能特征。
DOI：
10.1186/1750-1172-9-26
复制
发表时间：
2014-02-20
影响因子：
3.7
通讯作者：
De Baere E
中科院分区：
文献类型：
--
作者：
Verdin H;Sorokina EA;Meire F;Casteels I;de Ravel T;Semina EV;De Baere E
先天性白内障在临床上和遗传上是异质性的，有超过45个已知的位点和38个已鉴定的基因。它们可以作为孤立的缺陷发生，也可以与眼前节发育异常相关。PITX 3是先天性白内障伴或不伴眼前节发育不全（ASD）的疾病基因之一，其编码在透镜和眼前节发育中具有关键作用的转录因子。仅描述了五个独特的PITX 3突变，其中17-bp重复c.640_656dup，p.（Gly 220 Profs *95），是最常见的一种，也是已知的唯一一种引起ASD的白内障。本研究的目的是对5例常染色体显性遗传性先天性白内障（ADCC）和ASD先证者的PITX 3基因进行遗传学研究，比较其临床表现与先前报道的PITX 3相关表型，并对发现的PITX 3突变进行功能评估。对发现的PITX 3突变进行反式激活、DNA结合和亚细胞定位分析，眼科检查包括视力测量、裂隙灯生物显微镜、眼压测量和眼底镜检查。在4个比利时ADCC和ASD家族中，复发性17-bp重复c.640_656dup，p.（Gly 220 Profs *95），发现处于杂合状态。一种新的PITX 3突变c.573del，p.（Ser 192 Alafs *117），在比利时-罗马尼亚家族中鉴定为杂合子状态，具有相似的表型。功能分析表明，这种新的突变保留了其核定位，但导致DNA结合和反式激活活性降低，类似于重复。我们的研究确定了导致ASD先天性白内障的第二个PITX 3突变。我们的体外功能研究证实了表型表达的相似性，这些研究证明了新的p。（Ser 192 Alafs *117）和经常性p.（Gly 220 Profs *95）突变。
Congenital cataracts are clinically and genetically heterogeneous with more than 45 known loci and 38 identified genes. They can occur as isolated defects or in association with anterior segment developmental anomalies. One of the disease genes for congenital cataract with or without anterior segment dysgenesis (ASD) is PITX3, encoding a transcription factor with a crucial role in lens and anterior segment development. Only five unique PITX3 mutations have been described, of which the 17-bp duplication c.640_656dup, p.(Gly220Profs*95), is the most common one and the only one known to cause cataract with ASD. The aim of this study was to perform a genetic study of the PITX3 gene in five probands with autosomal dominant congenital cataract (ADCC) and ASD, to compare their clinical presentations to previously reported PITX3-associated phenotypes and to functionally evaluate the PITX3 mutations found. Sanger sequencing of the coding region and targeted exons of PITX3 was performed in probands and family members respectively. Transactivation, DNA-binding and subcellular localization assays were performed for the PITX3 mutations found. Ophthalmological examinations included visual acuity measurement, slit-lamp biomicroscopy, tonometry and fundoscopy. In four Belgian families with ADCC and ASD the recurrent 17-bp duplication c.640_656dup, p.(Gly220Profs*95), was found in a heterozygous state. A novel PITX3 mutation c.573del, p.(Ser192Alafs*117), was identified in heterozygous state in a Belgo-Romanian family with a similar phenotype. Functional assays showed that this novel mutation retains its nuclear localization but results in decreased DNA-binding and transactivation activity, similar to the recurrent duplication. Our study identified a second PITX3 mutation leading to congenital cataract with ASD. The similarity in phenotypic expression was substantiated by our in vitro functional studies which demonstrated comparable molecular consequences for the novel p.(Ser192Alafs*117) and the recurrent p.(Gly220Profs*95) mutations.
登录
查看更多内容
影响因子：
6.1
作者：
Ardayfio, Paul;Moon, JiSook;Kim, Kwang-Soo
通讯作者：
Kim, Kwang-Soo
影响因子：
4.4
作者：
Bidinost, C;Matsumoto, M;Traboulsi, EI
通讯作者：
Traboulsi, EI
影响因子：
3.1
作者：
Norris, RA;Kern, MJ
通讯作者：
Kern, MJ
DOI：
10.1002/ajmg.b.32020
发表时间：
2012-03-01
影响因子：
2.8
作者：
Derwinska, Katarzyna;Mierzewska, Hanna;Stankiewicz, Pawel
通讯作者：
Stankiewicz, Pawel
影响因子：
3.5
作者：
Jamieson, RV;Perveen, R;Black, GCM
通讯作者：
Black, GCM