Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations

<p>Abstract</p> <p>Background</p> <p>Poikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by <it>C16orf57 </it>mutations. To date 17 mutations have been identified in 31 PN patients.</p> <p>Results</p> <p>We characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novel <it>C16orf57 </it>mutations, c.232C>T and c.265+2T>G, as well as the already reported c.179delC, c.531delA and c.693+1G>T mutations. cDNA analysis evidences the presence of aberrant transcripts, and bioinformatic prediction of C16orf57 protein structure gauges the mutations effects on the folded protein chain.</p> <p>Computational analysis of the C16orf57 protein shows two conserved H-X-S/T-X tetrapeptide motifs marking the active site of a two-fold pseudosymmetric structure recalling the 2H phosphoesterase superfamily. Based on this model C16orf57 is likely a 2H-active site enzyme functioning in RNA processing, as a presumptive RNA ligase.</p> <p>According to bioinformatic prediction, all known <it>C16orf57 </it>mutations, including the novel mutations herein described, impair the protein structure by either removing one or both tetrapeptide motifs or by destroying the symmetry of the native folding.</p> <p>Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.</p> <p>Conclusions</p> <p>In cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening of <it>C16orf57 </it>gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.</p> <p>The bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function. Detection of aberrant transcripts, also in cells from PN patients carrying early truncated mutations, suggests they might be translatable. Tissue-specific sensitivity to the lack of functionally correct protein accounts for the main cutaneous and haematological clinical signs of PN patients.</p