Systematic search for neutropenia should be part of the first screening in patients with poikiloderma

Piard, Juliette; Holder‐Espinasse, Muriel; Aral, Bernard; Gigot, Nadège; Rio, Marlène; Tardieu, Marc; Puzenat, E.; Goldenberg, Alice; Toutain, Annick; Franques, Jérôme; MacDermot, K D; Bessis, Didier; Boute, Odile; Callier, Patrick; Gueneau, Lucie; Huet, Frédéric; Vabres, P.; Catteau, B.; Faivre, Laurence; Thauvin‐Robinet, Christel

doi:10.1016/j.ejmg.2011.07.004

Cited by 22 publications

(30 citation statements)

References 11 publications

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“…To date, 19 distinct C16orf57 mutations have been identified in 31 patients with PN (for details, see Supplemental Table S1; Arnold et al 2010;Tanaka et al 2010;Volpi et al 2010;Clericuzio et al 2011;Colombo et al 2012), all of which lead to the generation of truncated, and most likely nonfunctional, proteins. C16orf57 is also mutated in a subset of patients diagnosed with dyskeratosis congenita (DC) and Rothmund-Thomson syndrome (RTS) (Walne et al 2010;Piard et al 2012). Interestingly, DC and RTS share many similar clinical phenotypes with PN; however, mutations in C16orf57 can be used as molecular markers that allow for correct diagnosis (Piard et al 2012).…”

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confidence: 99%

“…C16orf57 is also mutated in a subset of patients diagnosed with dyskeratosis congenita (DC) and Rothmund-Thomson syndrome (RTS) (Walne et al 2010;Piard et al 2012). Interestingly, DC and RTS share many similar clinical phenotypes with PN; however, mutations in C16orf57 can be used as molecular markers that allow for correct diagnosis (Piard et al 2012). DC is often caused by mutations in factors involved in telomere maintenance (Armanios 2009), while RTS is primarily caused by mutations in the RECQL4 DNA helicase involved in DNA repair and replication (Larizza et al 2010).…”

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confidence: 99%

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C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification

et al. 2012

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C16orf57 encodes a human protein of unknown function, and mutations in the gene occur in poikiloderma with neutropenia (PN), which is a rare, autosomal recessive disease. Interestingly, mutations in C16orf57 were also observed among patients diagnosed with Rothmund-Thomson syndrome (RTS) and dyskeratosis congenita (DC), which are caused by mutations in genes involved in DNA repair and telomere maintenance. A genetic screen in Saccharomyces cerevisiae revealed that the yeast ortholog of C16orf57, USB1 (YLR132C), is essential for U6 small nuclear RNA (snRNA) biogenesis and cell viability. Usb1 depletion destabilized U6 snRNA, leading to splicing defects and cell growth defects, which was suppressed by the presence of multiple copies of the U6 snRNA gene SNR6. Moreover, Usb1 is essential for the generation of a unique feature of U6 snRNA; namely, the 39-terminal phosphate. RNAi experiments in human cells followed by biochemical and functional analyses confirmed that, similar to yeast, C16orf57 encodes a protein involved in the 29,39-cyclic phosphate formation at the 39 end of U6 snRNA. Advanced bioinformatics predicted that C16orf57 encodes a phosphodiesterase whose putative catalytic activity is essential for its function in vivo. Our results predict an unexpected molecular basis for PN, DC, and RTS and provide insight into U6 snRNA 39 end formation.

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C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification

et al. 2012

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“…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.…”

Section: Positive Clinical Predictive Value (Lifetime Risk To Developmentioning

confidence: 99%

“…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.…”

Section: Mutational Spectrummentioning

confidence: 99%

Clinical utility gene card for: poikiloderma with neutropenia

et al. 2013

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

2015

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Keywords: poikiloderma with neutropenia, RNA disease, splicing, U6 biogenesis, zebrafish Abbreviations: CHT, caudal haematopoietic tissue; CRISPR, clustered regularly interspaced short palindromic repeats; GFP, green fluorescent protein; hpf, hours post fertilization; MO, morpholino antisense oligo; MPN1, mutated in poikiloderma with neutropenia; PN; poikiloderma with neutropenia; snRNPs; small nuclear ribonucleoproteins; sqRT-PCR; semi-quantitative reverse transcription and polymerase chain reaction; USB1, U Six Biogenesis 1Poikiloderma with neutropenia (PN) is a rare inherited disorder characterized by poikiloderma, facial dysmorphism, pachyonychia, short stature and neutropenia. The molecular testing of PN patients has identified mutations in the C16orf57 gene, which encodes a protein referred to as USB1 (U Six Biogenesis 1). In this study, we developed a zebrafish model of PN by the microinjection of morpholino antisense oligos to suppress usb1 gene function. Severe morphological defects, including a bent tail, thin yolk extension and reduced body length, were predominant in the Usb1-suppressed embryos (morphants). We also observed significantly decreased number of neutrophils in the morphants by Sudan Black staining. Interestingly, the splicing of genes involved in neutrophil differentiation and development, such as mpx, ncf1, ela3l and npsn, was aberrant in the morphants. However, the splicing of haematopoietic precursors and erythroid-specific genes was unaltered. Importantly, the neutrophil defects were almost completely rescued by co-injection of ela3l mRNA, the most markedly affected gene in the morphants. Our study demonstrated a possible role of USB1 in modulating the tissue-specific gene splicing that eventually leads to the impaired development of neutrophils. This zebrafish model could serve as a valuable tool to investigate the causative role of USB1 in PN pathogenesis.

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Systematic search for neutropenia should be part of the first screening in patients with poikiloderma

Cited by 22 publications

References 11 publications

C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification

C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification

Clinical utility gene card for: poikiloderma with neutropenia

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

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