Abstract
Mutations in PITX2 have been implicated in several genetic disorders, particularly Axenfeld-Rieger syndrome. In order to determine the most reliable bioinformatics tools to assess the likely pathogenicity of PITX2 variants, the results of bioinformatics predictions were compared to the impact of variants on PITX2 structure and function. The MutPred, Provean, and PMUT bioinformatic tools were found to have the highest performance in predicting the pathogenicity effects of all 18 characterized missense variants in PITX2, all with sensitivity and specificity >93%. Applying these three programs to assess the likely pathogenicity of 13 previously uncharacterized PITX2 missense variants predicted 12/13 variants as deleterious, except A30V which was predicted as benign variant for all programs. Molecular modeling of the PITX2 homoedomain predicts that of the 31 known PITX2 variants, L54Q, F58L, V83F, V83L, W86C, W86S, and R91P alter PITX2’s structure. In contrast, the remaining 24 variants are not predicted to change PITX2’s structure. The results of molecular modeling, performed on all the PITX2 missense mutations located in the homeodomain, were compared with the findings of eight protein stability programs. CUPSAT was found to be the most reliable in predicting the effect of missense mutations on PITX2 stability. Our results showed that for PITX2, and likely other members of this homeodomain transcription factor family, MutPred, Provean, PMUT, molecular modeling, and CUPSAT can reliably be used to predict PITX2 missense variants pathogenicity.
Highlights
Paired-like homeodomain transcription factor 2 (PITX2, RefSeq NM 000325.5, MIM# 601542) is located at 4q25 and is expressed in the developing eye, brain, pituitary, lungs, heart, and gut [1]
Unlike most previous studies that focused on using only PolyPhen and SIFT to predict the pathogenicity of missense mutations, here, we investigated the predictive value of SIFT, PolyPhen and nine other prediction tools by comparing their predictions to in vitro functional data for PITX2 variants
The methods determined by this study to be preferred for analyses of PITX2 variants were those best able to distinguish both pathogenic and benign variants, yielding the highest accuracy
Summary
Paired-like homeodomain transcription factor 2 (PITX2, RefSeq NM 000325.5, MIM# 601542) is located at 4q25 and is expressed in the developing eye, brain, pituitary, lungs, heart, and gut [1]. Mutations in human PITX2 or the forkhead box transcription factor C1 (FOXC1; 6p25, RefSeq NM 001453.2, MIM# 601090) underlie the autosomal dominant disorder called Axenfeld-Rieger syndrome (ARS; MIM# 602482) [2–5]. ARS is a full penetrant, but clinically and genetically heterogeneous disorder characterized by developmental anomalies involving both ocular and non-ocular structures [6]. 87 mutations within the PITX2 gene have been.
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