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

Abstract

BackgroundPoikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by C16orf57 mutations. To date 17 mutations have been identified in 31 PN patients.ResultsWe characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novel C16orf57 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.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.According to bioinformatic prediction, all known C16orf57 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.Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.ConclusionsIn cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening of C16orf57 gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.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.

Clinical utility gene card for: poikiloderma with neutropenia

“…Of these 37 patients, 31 (84%) carry homozygous mutations, whereas the other six are compound heterozygous. 3 All identified mutations lead to the generation of truncated and most likely non-functional C16orf57 protein. C16orf57 is a 3 0 -5 0 exonuclease essential for the biogenesis of the splicing apparatus.…”

“…4,5 Several classes of mutations have been identified, listed here in order of decreasing prevalence: nonsense mutations (c.232C4T, c.243G4A, c.258T4A, c.267T4A, c.415C4T, c.541C4T, c.673C4T); small out-of-frame deletions (c.176_177delG, c.179delC, c.489_492del4, c.496delA, c.531delA, c.683_893 þ 1del12); and splicing alterations, including substitutions at canonical splice junctions or at splice-site consensus sequences (c.265 þ 2T4G, c.266 À1G4A, c.450 À2A4G, c.502A4G, c.504 À2A4C, c.693 þ 1G4T). 2,3,[6][7][8][9][10] No missense mutations have yet been found; c.502A4G can be categorised as a splicing alteration because it leads to the excision of the fourth exon from the mature C16orf57-001 transcript. 2 The most frequent recurrent mutations, c.531delA, c.496delA and c.179delC, reflect three geographical clusters.…”

“…Considering the very low frequency of PN syndrome and the prevalence of patients with homozygous mutations, common ancestry is the hypothesis most likely to explain the recurrence of these mutations in specific ethnic groups. 3 …”

“…Based on the literature, all patients reported so far develop the hallmark features of PN during the first year of life. In particular, the skin features may be apparent from the first months of life, 3,8 whereas other signs, such as pachyonychia, may develop later. Non-cyclic neutropenia, the hallmark haematologic sign, may be suspected due to susceptibility to recurrent infections (mainly pulmonary) during infancy, and should be confirmed by neutrophil count.…”

Incomplete splicing of neutrophil-specific genes affects neutrophil development in a zebrafish model of poikiloderma with neutropenia

“…3 The actual number of reported patients is quite limited, mostly because several PN patients have many similar clinical manifestations with dyskeratosis congenita and Rothmund-Thomson syndrome. 4,5 To date, 40 patients with PN have been reported, [6][7][8][9][10][11][12][13][14][15][16] containing 19 different mutations in the C16orf57 gene that encodes a 265-amino-acid protein, referred to as USB1 (U Six Biogenesis 1). 17,18 In some studies, this protein has also been referred to as MPN1 (Mutated in Poikiloderma with Neutropenia).…”