The PTPN12 gene encodes a phosphatase enzyme that is responsible for specifically dephosphorylating tyrosine-phosphorylated proteins. As tyrosine phosphorylation-mediated signaling is responsible for several processes such as cell proliferation, differentiation and mitosis, the PTPN12 enzyme plays a key regulatory role. It is involved in the negative regulation of the ERBB signaling pathway by dephosphorylating the cellular tyrosine kinase ERBB2. Other targets of PTPN12 include proteins related to cell adhesion and the cytoskeleton, thus suggesting a role in maintaining the cellular structure and mobility.
Interestingly, PTPN12 has also been found to dephosphorylate the product of the oncogene c-ABL, indicating a possible role in oncogenesis. Studies have in fact found a mutation in the PTPN12 gene associated with Colorectal Cancer, a heterogeneous somatic carcinoma affecting both men and women.
The PTPN12 gene is located on the long arm of chromosome 7. It spans a length of 102.7 kb of DNA and its coding sequence is spread across 19 exons. The gene encodes an 88 kDa protein product composed of 780 amino acids. Several additional isoforms of the PTPN12 protein exist due to alternatively spliced transcript variants. Expression of the gene has been seen in the nervous system, blood, intestine, liver and kidney. The missense mutation p.Lys61Arg has been associated with colorectal carcinoma.
Monies et al. (2017) studied the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient suffering from multiple epiphyseal dysplasia was subjected to whole exome sequencing. This helped identify a heterozygous mutation (c.904C>T, p.R302X) in exon 12 of the patient’s PTPN12 gene. This gene mutation was considered a candidate for pathogenicity as it was a novel truncating variant; and the PTPN12 gene is involved in the regulation of multimeric protein complexes in podosomes of osteoclasts. Further, the gene has a pLI score of 1, indicating that it is highly likely to be intolerant of loss-of-function mutations. Additional studies are required to independently confirm this association.
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