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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics

Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Hannah Verdin, Elena A Sorokina, Françoise Meire, Ingele Casteels, Thomy de Ravel, Elena V Semina, Elfride De Baere
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-26) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

HV carried out the molecular genetic studies and drafted the manuscript. EAS performed the immunocytochemistry, EMSA experiments and luciferase assays. FM, TDR and IC performed the ophthalmological examinations and provided clinical information. EVS and EDB participated in the design and coordination of the study, and helped to draft the manuscript. All authors read and approved the final manuscript.



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.
Additional file 1:PCR primers and conditions for molecular screening of PITX3 .(PDF 46 KB)
Additional file 2:Schematic representation of all reported mutated PITX3 proteins. The top diagram represents the wild-type PITX3 protein. The green box displays the homeodomain of 60 amino acids and the OAR (named after otp, aristaless and rax) domain of 14 amino acids is displayed by a blue box. The recurrent p.(Gly220Profs*95) and novel p.(Ser192Alafs*117) mutations are indicated in bold. The positions of the mutations are indicated with a red line and a red box displays the resulting aberrant protein segments. (PDF 392 KB)
Authors’ original file for figure 1
Authors’ original file for figure 2
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Authors’ original file for figure 5
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