Prox1 Gene Characterization and Mutational Analysis

Author Name(s): R. Lakshitaa
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Prox1 gene encodes for the homeo domain protein. It is the mammalian homologue of the gene prospero in Drosophila. The gene has a vital role in the development of brain structure and is crucial for learning and memory. In view of its importance the present work aims to use the Insilico tools and softwares to characterize this gene and the corresponding protein with special emphasis on the mutational sites. The gene and the protein sequences were retrieved from the NCBI data base for their further analysis. The gene characterization includes Promoter site identification, poly A site and Splice site detection, Motif analysis, prediction of the conserved sites. CpG Islands present in the gene sequence were predicted so as to find the most stable regions of the gene. Translation initiation sites were identified that can be help in predicting the frame of the gene product. This was followed by a focus on the mutation site prediction and analyzing its importance dictating the gene product. Possible Mutations in the prox1 gene are studied from SNPdb and Ensembl. The effects of these mutations on the translated product i.e, protein and its stability are analyzed using I-Mutant. SIFT was used to check the effect of these mutations on the normal function of protein. The effect of mutations on the onset of diseased condition was traced using PhdSNP. The ultimate outcome of the work is to establish the biologically important sites within the gene that can have a direct role in regulating the function of the gene product. The work can be a considerable support for the future research on the Prox 1 gene.


The homeobox gene prox1 is related to the Drosophila prospero gene, which mediates cell fate decisions of neuroblasts [1][2]. Prox1 has been found in many species such as Homo sapiens, Mus musculus, Rattus norvegicus, Gallus gallus and Danio rerio. Prox1 is the master gene of lymph angiogenesis [3] but is also expressed in the developing central nervous system [4], lens-secreting cone cells[5][6], R7 photoreceptors, and midgut. Furthermore, the expression is detected in embryonic hepatoblasts and in adult hepatocytes [7][8]. Prox1 controls cell proliferation and differentiation through different transcription pathways and has both oncogenic and tumor-suppressive functions.
Human Prox1 gene contains 736 amino acids. It contains two highly conserved domains one homeodomain and one prospero domain. Prox1 is a key player in normal development of a brain structure crucial for learning and memory and remains active throughout life; nurturing the cells vital for making new memories [9] .Prox1 is a transcription factor that functions like an on-off switch for genes. Researchers showed that by removing Prox1 at different stages of mouse development, the dentate gyrus fails to develop properly. Investigators also demonstrated that Prox1 remains important throughout mammalian life to ensure production of new granule cells, which are needed to form new memories. In this study, investigators determined that in the adult mammalian brain, Prox1 is active during a particular stage of differentiation when neural stem cells change from cells of unlimited potential to more specialized granule cells. The scientists reported that in the dentate gyrus Prox1 is produced by intermediate progenitor cells and that the lack of Prox1 results in death of these.


Prox1 gene of Homo sapiens was characterized. Gene annotation was done. Two potential exon regions were found which include 277-449 and 739-2817. Potential polyA site was predicted at position 2611 which is the site responsible for maintaining the stability of the gene. CpG Island was detected in the region 248 to 466 which infers that this is the region that is most stable in the entire sequence. Several Cis elements like TATA, GATA, LSF, Myf and Ets were found using Comet. Possible translation initiation sites were identified at positions 739,607,907,859 and 856 of PROX1 gene. Five domain regions were identified at the positions 1-143, 144-428, 429-564, 545-606, 608-733 of protein. Mutations were studied using Ensembl and SNPdb. The mutations at positions 32,124,186,280,301 decrease the stability of the protein. The mutations which had deleterious effects were studied using SIFT. The mutations at 32,186 and 280 were found have deleterious effects.
The mutation of C to A at the position 701 in the conserved region of gene would result in coding of glutamate instead of alanine in the protein at the position 32nd. The deleterious mutations 32,186 and 280 were further analyzed using PhdSNP, the effect of the mutation at position 32 is leading to the diseased condition .This mutation may affect the structural and functional properties of the protein affecting the CNS of Homo sapiens as PROX1 gene plays a major role in development of CNS. The work has highlighted all the regions of structural, functional and evolutionary importance in the gene as well as protein sequence of Prox 1 which can be a future scope for research in this domain.

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