In conclusion, the similar ADCC and ASD phenotypes resulting from both mutations could be explained by our in vitro functional studies.ĭNA constructs, cell culture and luciferase assays In vitro functional assays were performed for both mutations, showing similar functional characteristics. We identified the recurrent 17-bp duplication c.640_656dup, p.(Gly220Profs*95), in four of these families, and a novel PITX3 mutation c.573del, p.(Ser192Alafs*117), in a fifth family. The aim of this study was to analyze the PITX3 gene in five Belgian families with ADCC and ASD. Of particular note, homozygous PITX3 mutations were also described in two consanguineous pedigrees. Thus far, only the 17-bp duplication has been associated with ASD all other mutations are reported with isolated cataract. The other recurrent mutation is a 1-bp deletion at position 650, p.(Gly217Alafs*92), found in two families. Two of these mutations are recurrent, the most common one being the 17-bp duplication p.(Gly220Profs*95) which was reported in eight of the 13 families. Since the original gene identification study, there have been only a few additional mutations identified, bringing the total number of unique PITX3 mutations found in ADCC with or without ASD to five mutations in 13 different families.
A 17-bp duplication c.640_656dup, p.(Gly220Profs*95), was found in a family with ADCC and ASD while a missense mutation c.38G > A, (Ser13Asn), was identified in a second family. Before this finding, the first human PITX3 mutations had already been identified in two families with autosomal dominant congenital cataract (ADCC).
Two different deletions in the promoter region of Pitx3 were later found to explain the ak phenotype. Consequently, Pitx3 was the top candidate for the ak phenotype but no mutation was found in the coding region of Pitx3. The lens develops normally in ak mice until an arrest occurs around embryonic days 10.5–11 corresponding to the moment of initial expression of Pitx3 in the lens. Interestingly, Pitx3 mapped to the aphakia ( ak) locus, a recessive mutation resulting in bilateral microphthalmia with lens aplasia originally described by Varnum and Stevens in 1968. The conserved 14-amino acid OAR motif, named after the homeodomain proteins otp, aristaless, and rax, is located downstream of this homeodomain, and may function in the target specificity and transactivation of the homeodomain protein. Like the other members of this family, PITX3 contains a characteristic and strongly conserved homeodomain required for DNA binding. The PITX protein family is a subfamily of the paired-like class of the homeobox-containing proteins, which play a crucial role in the development of different organisms including mammals. PITX3 was isolated as the third gene of the PITX homeobox-containing transcription factor gene family, along with PITX1 and PITX2. 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. ASD is an umbrella term for the spectrum of developmental disorders affecting the structures of the anterior segment of the eye.
Mutations in genes encoding proteins important in the development and maintenance of the structural integrity of the lens such as crystallins, connexins and aquaporins are typically associated with isolated congenital cataracts while mutations in the transcription factor genes PAX6, FOXE3, EYA1, MAF, and PITX3 have been described in congenital cataract with anterior segment dysgenesis (ASD). Congenital cataract is clinically and genetically heterogeneous with about 45 loci known and 38 genes identified. Congenital cataract manifests in the first year of life the estimated incidence of congenital cataract is 72 per 100,000 children in developed countries with a higher incidence in less-developed countries. It is the primary cause of blindness worldwide and is classified into different types based on the age of onset. Cataract is defined as opacity or cloudiness of the crystalline lens.
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