The AGTPBP1 gene, also known as CCP1, encodes a zinc carboxypeptidase enzyme that is responsible for catalysing the deglutamylation of target proteins. CCP1 can carry out the deglutamylation of polyglutamate side chains added by post-translational modification to the C-termini of tubulin proteins. It can also mediate the deglutamylation of gene-encoded polyglutamates from proteins such as MYLK.
Mouse models have helped elucidate the physiological role of CCP1. The mouse orthologue gene, Ccp1, is found to be mutated in the Purkinje cell degeneration (pcd) phenotype of mice. These pcd mice exhibit ataxia subsequent to cerebellar Purkinje cell degeneration. They also suffer the progressive deterioration of thalamic neurons, retinal photoreceptors and olfactory bulb mitral cells. Analysis of pcd mice has shown increased levels of tubulin polyglutamylation in the brain.
The AGTPBP1 gene is located on the long arm of chromosome 9 at position 9q21.33. The gene spans a length of 195.4 kb of DNA and its coding sequence is spread across 31 exons. Several additional isoforms of the AGTPBP1 gene exist due to alternatively spliced transcript variants. While the gene is widely expressed in the human body, overexpression is seen in the fetal brain, retina and peripheral blood mononuclear cells.
Monies et al. (2017) analyzed the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 2-year-old female, presented with congenital hypotonia and global developmental delay. She was found to suffer from diffuse atrophic changes of the brain indicated by diminished myelinated white matter volume, deepened sulci, dilated ventricular system, thinned corpus callosum, increased mamillo-potine distance and significantly prominent extra axial CSF spaces. Using WES, a homozygous mutation (c.2908C>T, p.R970W) was identified in exon 20 of the patient’s AGTPBP1 gene. This gene mutation was considered a candidate for pathogenicity as it was a novel variant located within the autozygome that was predicted to be deleterious, and mutations in the mouse orthologue of the AGTPBP1 gene have been shown to result in cerebellar Purkinje neuron degeneration. The authors noted that further studies are required to independently confirm this association.
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