The Peptidyl-tRNA Hydrolase 2 (PTRH2) gene codes for a highly conserved mitochondrial protein. This protein prevents the accumulation of dissociated peptidyl-tRNA, and plays an important role in regulating cell survival and death. It promotes cell survival as part of an integrin-signaling pathway for cells attached to the extracellular matrix (ECM), through interaction with focal adhesion kinase (FAK) and subsequent activation of the PI3K-AKT-NFkB pathway. It also induces Bcl-2 transcription that blocks the intrinsic mitochondrial apoptotic pathway. PTRH2 functions as a phosphoprotein that regulates NFkB and ERK signaling. In cells that have lost their attachment to the ECM through anoikos, PTRH2 promotes apoptosis. Upon loss of integrin-mediated cell attachment to the ECM, PTRH2 protein is phosphorylated, is released from the mitochondria into the cytosol, and promotes apoptosis through interactions with transcriptional regulator amino-terminal enhancer of split (AES).
Defects in this protein have been associated with Infantile Multisystem Neurologic, Endocrine, and Pancreatic disease (INMEPD)., a progressive multisystem disease characterized by intellectual disability, progressive cerebellar atrophy, postnatal microcephaly, failure to thrive, hearing impairment, polyneuropathy, and organ fibrosis with exocrine pancreas insufficiency.
The PTRH2 gene is located on the long arm of chromosome 17. It consists of only one coding exon, spanning about 33 kb within the genomic DNA. The encoded protein comprises 179 amino acids with a molecular mass of 19 kDa. The protein consists of two putative domains, an N-terminal mitochondrial localization sequence, and a UPF0099 domain. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
Picker-Minh et al., (2016) descried five patients from two consanguineous Tunisian and Saudi families. Almost all patients presented with neurological features including intellectual disability, ataxia, motor delay, severe speech delay, and sensorineural hearing loss. Also they all had exocrine pancreatic insufficiency with reduced pancreas elastase levels that was partly associated with failure to thrive in the first years of life and consecutive deficiency of lipophilic vitamins. A homozygous missense mutation, c.254A > C in exon 2 of the PTRH2 gene, was detected in all affected patients. This mutation resulted in an amino acid exchange of glutamate to proline (p.Q85P), which altered the hydrogen bridge bonds within the protein and putatively affected structure, folding, and stability of PTRH2.
See: [Saudi Arabia> Picker-Minh et al., (2016)]