Bhattacharya, S

Giovanna, A

Shah, A

Waseem, NH

UCL Discovery

“New insights into the biological role of VAX2 in human, in health and disease”Giovanna Alfano1, Amna Z. Shah1, Naushin H. Waseem 1, Andrew R. Webster1,2 and Shomi S. Bhattacharya1    1Institute of Ophthalmology, UCL, London EC1V 9EL, UK2Moorﬁelds Eye Hospital, London EC1V 2PD, UKPurpose: VAX2 (MIM 604295) is a transcription factor expressed in the ventral region of the prospective neural retina in vertebrates and is required for ventral eye specification. Its genetic inactivation in mouse leads to an incompletely penetrant ocular coloboma. Based on the similarities between the mutant mouse phenotype and the clinical features of isolated coloboma in human, VAX2 represents a good candidate gene for this human condition. Thus far, however, no mutations affecting VAX2 in coloboma patients have been reported. Interestingly, recently it has been shown that Vax2 in mouse plays a key role in ensuring appropriate gene expression in cone photoreceptor cells. Despite a wide range of studies in vertebrates its function in human is still poorly understood. This study was undertaken to better elucidate the role of VAX2 in human in health and disease.Methods: VAX2 transcripts were obtained by RT-PCR on cDNA from human tissues and cultured cells. These transcripts were sub-cloned into mammalian expression vectors for in vitro analysis. Variant proteins were generated by site-directed mutagenesis. A cohort of cone-rod dystrophy patients was screened for variant identification using Sanger sequencing.Results: It was observed that VAX2 is highly expressed in neuronal tissues and cultured cell lines. Two spliced variants were detected: isoform-1 (NM_012476), and a novel transcript (isoform-2), mainly expressed in retina and predicted to encode a shorter protein of 150 amino acids. In vitro exogenous expression of tagged protein isoforms showed differential localization potentially underlying distinct biological roles. Isoform-1 localizes to the nucleus while isoform-2 is widespread throughout the cell. The involvement of Vax2 in cone specific gene expression suggested screening of patients with cone-rod dystrophy. Sequence analysis revealed a heterozygous change c.416T>G (p.Leu139Arg) in one patient. Characterization of this variant showed damaging effects on protein localisation and is therefore suggestive of a functional defect, with potential involvement in the disease phenotype.  Conclusions: Our data suggest that in addition to being a transcription factor VAX2 could be involved in other molecular pathways due to the short isoform in the human. Moreover, VAX2 may be involved in cone photoreceptor cell biology. In summary, our findings raise new questions about the VAX2 gene and its biological role in health and disease.

New insights into the biological role of VAX2 in human, in health and disease

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UCL Discovery