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Figure 5 | Orphanet Journal of Rare Diseases

Figure 5

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

Figure 5

Structural implications of C16orf57 mutations in PN patients. Predicted disruption of protein structure caused by 19 C16orf57 mutations (references in the first column). The N- and C-terminal sequence repeats detected by HHrep are encoded by similar exon arrays (exons 2-4 and 5-7, respectively). The correspondence between gene exons and protein domains (using the topology map of Figure 4 with similar colours and labels) is pointed out focusing on the two H-X-S motifs (grey vertical bars) that form the C16orf57 catalytic site. The top eight mutations lead to loss of both H-X-S motifs as they predict early truncation by a stop codon (c.232C>T, c.243G>A, c.258T>A and c.267T>A), frameshift (c.176_177delGG, c.179delC) or missplicing leading to frameshift (c.265+2T>G, c.266-1G>A). Six subsequent mutations terminate the protein chain before the second H-X-S motif: they include nonsense c.415C>T and c.541C>T, frameshift c.489_492del4, c.496delA and c.531delA and splice site mutation c.504-2A>C. Two mutations lead to the loss of the second H-X-S domain by inframe exon 6 skipping caused by frameshift, c.683_693+1del12, or missplicing, c.693+1G>T. Splicing c.450-2A>G and c.502A>G mutations should maintain both the key motifs, but due to inframe exon 4 skipping the protein loses a critical structural element and likely can not fold properly. Lastly, the c.673C>T stop mutation predicts a shorter chain endowed with both catalytic motifs, but unable to complete the active structure. Prediction of the effects of the different mutations is made more complex by the homozygous versus the heterozygous state. Black arrowheads indicate mutations found in the homozygous state while red arrowheads those found in the heterozygous state; the colour-code of the # symbol is according to the partnership.

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