The AK5 gene encodes an enzyme belonging to the adenylate kinase family. Specifically, AK5 is a nucleoside monophosphate (NMP) kinase that is responsible for the phosphorylation state of intracellular adenine nucleotide. Substrate specificity is determined by the phosphate donor; AK5 phosphorylates AMP and dAMP when ATP is the donor, while it acts on AMP, CMP and dCMP when GTP is the donor. The enzyme is localized to the cytosol and is made up of two 2 catalytic adenylate kinase domains known as AK5p1 and AK5p2. Both domains consist of a glycine-rich p-loop, an NMP-binding domain, and a LID domain.
Recent studies have shed light on the pathological effect of AK5 mutations. The gene has been suspected to play a role in haemolytic anemia as well as in autoimmune-mediated limbic encephalitis.
The AK5 gene is located on the short arm of chromosome 1. It spans a length of 277.9 kb of DNA and its coding sequence is contained within 16 exons. The protein product encoded by this gene has a molecular mass of 63.3 kDa and consists of 562 amino acids. Several additional isoforms of the AK5 protein exist due to alternatively spliced transcript variants. The gene is found to be overexpressed in the brain.
Al-Aama et al. (2017) investigated the underlying genetic defect in a consanguineous Saudi family affected by Celiac Disease (CD). The 21-year-old female proband from this family suffered from type 1 diabetes mellitus. She and her younger sister both tested positive for endomysial antibodies and a CD diagnosis was confirmed by a duodenal biopsy. Except for mild abdominal pain in the younger sister, neither patient had any other symptoms. Whole Exome Sequencing (WES) helped uncover a homozygous insertion c.1683_1684insATT, in the AK5 gene that segregated in an autosomal recessive manner in the family. However, further validation was carried out using 100 CD-affected Saudi patients and 100 healthy Saudi controls. Interestingly, the mutation was found to be highly penetrant in Saudi Arabians (Saudi MAF=0.62, ExAC MAF=0.000008) and was seen to modify the risk of the healthy Saudi population against CD development (p<0.002). This was further consolidated by in-silico analysis which predicted the mutation to induce a gain-of-function in the kinase activity of AK5, potentially down-regulating CD4+ T-cell reactivity against gluten antigens. The authors hence stressed the importance of using population-specific variant databases to prevent false leads.
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