Targeted Next-Generation Sequencing Appoints C16orf57 as Clericuzio-Type Poikiloderma with Neutropenia Gene

Università degli Studi di Milano, Dipartimento di Biologia e Genetica per le Scienze Mediche, Milan, Italy.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2009; 86(1):72-6. DOI: 10.1016/j.ajhg.2009.11.014
Source: PubMed


Next-generation sequencing is a straightforward tool for the identification of disease genes in extended genomic regions. Autozygosity mapping was performed on a five-generation inbred Italian family with three siblings affected with Clericuzio-type poikiloderma with neutropenia (PN [MIM %604173]), a rare autosomal-recessive genodermatosis characterised by poikiloderma, pachyonychia, and chronic neutropenia. The siblings were initially diagnosed as affected with Rothmund-Thomson syndrome (RTS [MIM #268400]), with which PN shows phenotypic overlap. Linkage analysis on all living subjects of the family identified a large 16q region inherited identically by descent (IBD) in all affected family members. Deep sequencing of this 3.4 Mb region previously enriched with array capture revealed a homozygous c.504-2 A>C mismatch in all affected siblings. The mutation destroys the invariant AG acceptor site of intron 4 of the evolutionarily conserved C16orf57 gene. Two distinct deleterious mutations (c.502A>G and c.666_676+1del12) identified in an unrelated PN patient confirmed that the C16orf57 gene is responsible for PN. The function of the predicted C16orf57 gene is unknown, but its product has been shown to be interconnected to RECQL4 protein via SMAD4 proteins. The unravelled clinical and genetic identity of PN allows patients to undergo genetic testing and follow-up.

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Available from: Ludovica Volpi
    • "The function of the 2H domain in UBASH3 is unknown (Tsygankov, 2013). USB1 is linked to a rare hereditary disease, poikiloderma with neutropenia, and functions in the maturation of the U6 snRNA (Colombo et al., 2012; Hilcenko et al., 2013; Volpi et al., 2010; Walne et al., 2010). This enzyme catalyzes the cleavage of the phosphodiester bond between the two terminal nucleotides in the substrate and forms a product with a 2′,3′-cyclic end (Hilcenko et al., 2013). "
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    ABSTRACT: 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) is an abundant membrane-associated enzyme within the vertebrate myelin sheath. While the physiological function of CNPase still remains to be characterized in detail, it is known – in addition to its in vitro enzymatic activity – to interact with other proteins, small molecules, and membrane surfaces. From an evolutionary point of view, it can be deduced that CNPase is not restricted to myelin-forming cells or vertebrate tissues. Its evolution has involved gene fusion, addition of other small segments with distinct functions, such as membrane attachment, and possibly loss of function at the polynucleotide kinase-like domain. Currently, it is unclear whether the enzymatic function of the conserved phosphodiesterase domain in vertebrate myelin has a physiological role, or if CNPase could actually function – like many other classical myelin proteins – in a more structural role.
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    • "All strains were maintained according to standard laboratory procedures. Lymphoblastoid cell lines ML07136M (P1 in the text) derived from a PN patient and GGB04410M (R1) derived from P1's healthy brother were obtained from Galliera Genetic Bank (Genova, Italy) and were previously described [7] [8]. "
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    ABSTRACT: Mpn1 is an exoribonuclease that modifies the spliceosomal small nuclear RNA (snRNA) U6 by trimming its oligouridine tail and introducing a cyclic phosphate group (>p). Mpn1 deficiency induces U6 3' end misprocessing, accelerated U6 decay and pre-mRNA splicing defects. Mutations in the human MPN1 gene are associated with the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Here we present the deep sequencing of the >p-containing transcriptomes of mpn1Δ fission yeast and PN cells. While in yeast U6 seems to be the only substrate of Mpn1, human Mpn1 also processes U6atac snRNA. PN cells bear unstable U6atac species with aberrantly long and oligoadenylated 3' ends. Our data corroborate the link between Mpn1 and snRNA stability suggesting that PN could derive from pre-mRNA splicing aberrations. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jul 2015 · FEBS letters
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    • "The diagnosis of our PN patients were made clinically and confirmed by molecular analysis for deleterious mutations in the causative gene, USB1, identified recently in 2010 [Volpi et al., 2010]. c.531delA homozygous deleterious mutation was detected in both patient's genomic DNA (Fig. 2C,D). "
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    ABSTRACT: Poikiloderma with neutropenia (PN), is a rare genodermatosis associated with patognomic features of poikiloderma and permanent neutropenia. Three common recurrent mutations of related gene, USB1, were considered to be associated with three different ethnic origins. The most common recurrent mutation, c.531delA, has been detected in seven Caucasian patients in the literature. In this paper, we present review of all patients from the literature and report two additional patients of Turkish ancestry with the diagnosis of PN. The diagnosis of these two PN patients were made clinically and confirmed by molecular analysis which detected the most common recurrent mutation, c.531delA. Genotype-ethnic origin correlation hypothesis, therefore, has been strengthened with this result. Short stature in PN, is a common finding, which until now has never been treated with growth hormone (GH). One of our patients is the first patient with attempted treatment of short stature via GH administration. Finally, both of our patients had high-pitched voice and vocal cord nodules which might be considered as additional clinical findings not associated with PN before. © 2014 Wiley Periodicals, Inc.
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