The MTDH gene, which encodes the Metadherin protein, acts as an oncogene and its altered expression has been associated with carcinogenesis of the liver, brain, skin and breast as well as metastasis in the lung and bone. Metadherin is able to carry out its oncogenic action through several pathways. As a transcription coactivator, it modulates the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis and senescence. It thus positively regulates angiogenesis and autophagy while inhibiting apoptosis.
Specific pathways regulated by MTDH include lipopolysaccharide-mediated signaling, protein kinase B signaling and I-kappaB kinase/NF-kappaB signaling. MTDH positively regulates NF-kappaB transcription factor activity and by activating the NF-kappaB signaling pathway, it is believed to play a role in the chronic inflammatory changes seen prior to hepatocellular carcinoma. Metadherin also interacts with PLZF, a protein that regulates the expression of genes involved in cell growth and apoptosis. By reducing PLZF binding to promoters, MTDH is able to reduce PLZF-mediated repression, thus evading apoptosis and increasing cell growth.
The MTDH gene is located on the long arm of chromosome 8. It spans a length of 86.1 kb of DNA and its coding sequence is spread across 13 exons. It encodes a 63.8 kDa protein product composed of 582 amino acids. While the gene is found to be ubiquitously expressed in the human body, overexpression is seen in the muscular organs, including the skeletal muscle, heart, tongue, and small intestine and in endocrine glands, such as the thyroid and adrenal gland.
Monies et al. (2017) examined the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, an 11-year-old male, presented with growth retardation/short stature, fine and gross motor delay, speech delay, intellectual disability, learning disability and developmental regression. He was also diagnosed with autism spectrum disorder, and displayed autistic features, stereotypic behaviors and other psychiatric symptoms. Whole exome sequencing helped identify a homozygous mutation (c.862delG, p.E288fs) in exon 6 of the patient’s MTDH gene. This gene mutation was considered a candidate for pathogenicity as it was a homozygous truncation; and the MTDH gene is expressed in the brain and has previously been studied in the context of glioma. Additional studies are required to independently confirm this association.
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