The MTPAP gene encodes an enzyme belonging to the DNA polymerase type-B-like family. The polymerase is responsible for the processes of mRNA polyadenylation, and synthesis of 3’ homopolymeric poly(A) extensions on mitochondrial mRNA transcripts. In vitro studies have found that knockdown of the MTPAP gene leads to extreme shortening of the poly(A) tails on mitochondrial mRNAs. MTPAP is also involved in the replication-dependent histone mRNA catabolic process.
The gene is associated with Spastic Ataxia 4, Autosomal Recessive (SPAX4), a neurodegenerative disorder characterized by progressive cerebellar ataxia, spastic paraparesis, dysarthria, and optic atrophy.
The MTPAP gene is located on the short arm of chromosome 10. It spans a length of 64 kb of DNA and its coding sequence is contained in nine exons. The protein product encoded by this gene has a molecular mass of 66 kDa and consists of 582 amino acids. An additional isoform of the MTPAP protein exists due to alternative splicing and contains 712 amino acids. The gene is found to be overexpressed in the lungs, breast, testes and peripheral blood mononuclear cells. Homozygous mutations in the MTPAP gene are associated with spastic ataxia 4. So far, a 1432A-G transition in exon 9 of MTPAP, resulting in a N478D substitution, has been linked to the disorder.
Al-Shamsi et al. (2016) investigated a cohort of 85 patients seen at a metabolic center in Abu Dhabi. The patients could not be diagnosed using conventional methods, hence Whole Exome Sequencing (WES) was carried out. This helped definitively diagnose 50% of the cases in the cohort. One patient in the study suffered from developmental delay and regression starting at 8 months of age. WES uncovered a homozygous variant of unknown significance (c.1468G > T, p.V490L) in the patient’s SPAX4 gene. The variant was confirmed to be pathogenic due to a consistent phenotype, biochemical findings, segregation studies and reported pathogenicity.
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