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, Oct 03, 2015
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    • "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.
    Brain Research 09/2015; DOI:10.1016/j.brainres.2015.09.004 · 2.84 Impact Factor
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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.
    American Journal of Medical Genetics Part A 10/2014; 164(10). DOI:10.1002/ajmg.a.36683 · 2.16 Impact Factor
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    • "sequencing (NGS), either in combination with whole-exome capture or targeted capture of specific genomic regions, or used to directly sequence the entire genome (WGS) (Lupski et al., 2010; Ng et al., 2009; Volpi et al., 2010). Whole-exome sequencing was also successfully employed to identify a human CLCN7 mutation in osteopetrosis patients (Sui et al., 2013). "
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    ABSTRACT: Chloride/proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue Cattle with a severe symptomatology including peri-natal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption.
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