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

Elisa A Colombo,Lidia Larizza,Gloria Negri,J Fernando Bazan,Anna Teti,Matteo Luciani,Cristina Gervasini,Spencer K Sullivan,Umram Cetincelik,Albert C Yan,Andrea Del Fattore,Nursel H Elcioglu,Ludovica Volpi,Deniz Yucelten,Ilknur Altunay

doi:10.1186/1750-1172-7-7

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.

Highlights

Poikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by C16orf57 mutations
Following discovery of the causative gene [6] and molecular evidence for distinct genetic control between PN and Rothmund-Thomson syndrome (RTS; OMIM#268400) [7], 31 PN patients have been tested and found to bear 17 different mutations in the responsible C16orf57 gene, 84% of the patients were found in the homozygous state [6,8,9,10,11,12] and only six were compound heterozygous [6,11,13]
The cohort comprises two previously described cases, one Italian girl (#21) with the association of Osteopetrosis with Poikiloderma [23] and one young adult male (#26) from Turkey diagnosed as Rothmund-Thomson [24], and four patients of novel description from North Africa (#11), US (#25) and Turkey (#16, #17a), respectively

Summary

Introduction

Poikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by C16orf mutations. Biallelic mutations of the C16orf (OMIM*613276) gene underlie Poikiloderma with Neutropenia (PN; OMIM#604173), an inherited genodermatosis characterized by early onset poikiloderma, pachyonychia, palmoplantar hyperkeratosis, skeletal defects and non-cyclic neutropenia This condition results in recurrent infections during infancy and childhood, primarily of a pulmonary nature, and contributes to the postnatal growth delay in weight and height of the patients. Following discovery of the causative gene [6] and molecular evidence for distinct genetic control between PN and Rothmund-Thomson syndrome (RTS; OMIM#268400) [7], 31 PN patients have been tested and found to bear 17 different mutations in the responsible C16orf gene, 84% of the patients were found in the homozygous state [6,8,9,10,11,12] and only six were compound heterozygous [6,11,13] This cohort includes patients previously diagnosed as affected with Dyskeratosis Congenita (DC; OMIM#224230) and with Rothmund-Thomson syndrome illustrating significant phenotypic overlap among these entities [10,13]. Despite the limited mutational repertoire a few recurrent mutations have been identified, including c.496delA, common among those of Athabaskan ancestry [11], c.531delA in Turkish families [10,12] and c.179delC in patients of North African origin [8,12], consistent with founder mutations restricted to different geographic areas

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