DPH1 (diphthamide biosynthesis 1, OMIM*603527) is located on chromosome 17p13.3, with a of 13.8kb and consists of 13 exons.
It encodes the enzyme [2-(3-amino-3-carboxypropyl) histidine synthase subunit 1] which is required for the synthesis of diphthamide and is essential for generating the diphthamide modification on eukaryotic translation elongation factor 2 (EEF2). Diphtheria toxin (DT) catalyzes the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to diphthamide, thus inhibiting the protein synthesis and leading to cell death. DPH1 protein has an important role in regulation of cell proliferation, tumorigenesis, and embryonic development.
DPH1 is a tumor suppressor gene as its underexpression in somatic tissue correlates with the development of both ovarian and breast cancer. Its modulation by microRNA was proposed to exert a regulatory axis during colorectal cancer tumorigenesis. Up till now, no patients with germline DPH1 mutations were reported to have tumor tendency.
Type of mutations
Loss of function of DPH1 gene is the proposed disease mechanism. However, majority of reported variants are missense. No definite genotype-phenotype correlation has been delineated. It was proposed that for those missense variants, a strong alteration in protein structure and functionality by in silico models may lead to more severe disease phenotype, e.g. p.Leu125Pro.
Most of the reported variants are inherited from unaffected parents who are the heterozygous carriers. Germline mosaicism has not been reported so far.
Diagnostic testing
DPH1 disease causing variants can be identified by exome/ genome sequencing.
DPH1