Abstract
BackgroundCongenital 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.MethodsSanger 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.ResultsIn 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.ConclusionsOur 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.
Highlights
Congenital cataracts are clinically and genetically heterogeneous with more than 45 known loci and 38 identified genes
Mutations in genes encoding proteins important in the development and maintenance of the structural integrity of the lens such as crystallins, connexins and aquaporins [1,2] are typically associated with isolated congenital cataracts while mutations in the transcription factor genes PAX6 [3], FOXE3 [4], EYA1 [5], MAF [6], and PITX3 [7] have been described in congenital cataract with anterior segment dysgenesis (ASD)
The first Belgian family is a three-generation family with four affected individuals diagnosed with posterior subcapsular cataract (PSC) (Figure 3A)
Summary
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. Congenital cataract is clinically and genetically heterogeneous with about 45 loci known and 38 genes identified. Mutations in genes encoding proteins important in the development and maintenance of the structural integrity of the lens such as crystallins, connexins and aquaporins [1,2] are typically associated with isolated congenital cataracts while mutations in the transcription factor genes PAX6 [3], FOXE3 [4], EYA1 [5], MAF [6], and PITX3 [7] have been described in congenital cataract with anterior segment dysgenesis (ASD). The ocular anomalies typically include corneal opacity, adhesions between the iris and cornea or lens and cornea, iris hypoplasia, corectopia or polycoria, and malformation of the irido-corneal angle drainage structures [8]
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