Identification of a Novel C16orf57 Mutation in Athabaskan Patients With Poikiloderma With Neutropenia

Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 02/2011; 155A(2):337-42. DOI: 10.1002/ajmg.a.33807
Source: PubMed


Poikiloderma with Neutropenia (PN), Clericuzio-Type (OMIM #604173) is characterized by poikiloderma, chronic neutropenia, recurrent sinopulmonary infections, bronchiectasis, and nail dystrophy. First described by Clericuzio in 1991 in 14 patients of Navajo descent, it has since also been described in non-Navajo patients. C16orf57 has recently been identified as a causative gene in PN. The purpose of our study was to describe a spectrum of C16orf57 mutations in a cohort of PN patients including five patients of Athabaskan (Navajo and Apache) ancestry. Eleven patients from eight kindreds were enrolled in an IRB-approved study at Baylor College of Medicine. Five patients were of Athabaskan ancestry. PCR amplification and sequencing of the entire coding region of the C16orf57 gene was performed on genomic DNA. We identified biallelic C16orf57 mutations in all 11 PN patients in our cohort. The seven new deleterious mutations consisted of deletion (2), nonsense (3), and splice site (2) mutations. The patients of Athabaskan ancestry all had a common deletion mutation (c.496delA) which was not found in the six non-Athabaskan patients. Mutations in the C16orf57 gene have been identified thus far in all patients studied with a clinical diagnosis of PN. We have identified seven new mutations in C16orf57 in PN patients. One of these is present in all patients of Athabaskan descent, suggesting that c.496delA represents the PN-causative mutation in this subpopulation.

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    • "PN is also characterized by chronic neutropenia and bone marrow abnormalities associated with infection of the respiratory system and, eventually, myelodysplasia and risk of leukemic transformation. Rarely, PN is also associated with squamous cell carcinoma [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. The actual number of reported patients is quite limited, mostly because several PN patients have been previously misdiagnosed with dyskeratosis congenita or Rothmund–Thomson syndrome as a result of the large overlap of the clinical manifestations of these syndromes [7] [10]. "
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    ABSTRACT: Recent studies from independent laboratories have decisively disclosed the identity of the long-sought 3-5' RNA exonuclease that trims posttranscriptionally the oligouridine tail of U6, which is the small catalytic non-coding RNA promoting premRNA splicing within the spliceosome. This exonuclease, dubbed Mpn1 or Usb1, is a highly conserved enzyme that specifically removes uridines from the 3' end of U6, and directly generates terminal 2',3' cyclic phosphate groups. Mutations in the human gene encoding hMpn1 have been reported in patients diagnosed with the rare genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1-associated functions in U6 small nuclear RNA posttranscriptional regulation suggest the existence of sophisticated cellular pathways involved in surveillance and stabilization of U6. In this light, PN pathology might turn out to be a consequence of disturbed quality control of RNAs involved in crucial biological events.
    Preview · Article · May 2013 · FEBS letters
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    • "C16orf57 encodes a protein of unknown molecular function . 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). "
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    ABSTRACT: 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 3'-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 2',3'-cyclic phosphate formation at the 3' 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 3' end formation.
    Full-text · Article · Aug 2012 · Genes & development
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    • "The syndrome was first described by Clericuzio in Navajo Indians [1] and subsequently in patients of Caucasian ancestry from different geographic areas [2-5]. 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 [6,8-12] and only six were compound heterozygous [6,11,13]. Interestingly 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]. All the identified mutations, six nonsense, six frameshifts and five splicing mutations including the apparent missense change, c.502A>G [6], lead to loss-of-function. "
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    ABSTRACT: Poikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by C16orf57 mutations. To date 17 mutations have been identified in 31 PN patients. We 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. In 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.
    Full-text · Article · Jan 2012 · Orphanet Journal of Rare Diseases
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