| || Figure 2. Schematic representation of exon-intron structure of USB1 and the two major transcripts resulting from alternative splicing of the two mutually exclusive exons 4.|
|Description|| According to UCSC database (GRCh37/hg19, Feb.2009), USB1 gene maps in the region between 58035277 and 58055527 bp from pter of chromosome 16 with a centromeric-telomeric orientation. |
It spans 20 kb and is composed of seven exons (GI:305855061; NM_024598.3) (Fig.2).
|Transcription|| Two physiological isoforms, generated by alternative splicing (Fig. 2), have been detected in normal samples (leucocytes, keratinocytes, melanocytes and fibroblasts). The major transcript of 2282 nt (isoform 1, NM_024598.3) includes all the seven exons of the gene, while the shorter isoform of 1217 nt (NM_001204911.1) comprises the first three exons and an alternative terminal fourth exon located in IVS3 (Arnold et al., 2010). |
Several additional transcripts, a few detected in cancer samples, are reported in the Ensembl database.
|Pseudogene|| No pseudogene for USB1 is known.|
| || Figure 3. Ribbon model of the USB1 protein showing its globular symmetrical conformation with two lobes separated by a central groove that exposes the catalytic site containing the two HLSL motifs (encircled). The terminal lobe comprises both the N- and the C-termini. Both the terminal and transit lobe consist of antiparallel β-sheets and α-helices (modified from Colombo et al., 2012).|
|Description|| The crystal structure of the human USB1 protein, translated by isoform 1 mRNA has been recently resolved (Hilcenko et al., 2013).The main USB1 protein comprises 265 aa, while translation of isoform 4 mRNA predicts a 186 amino acid protein with a different C-terminus. |
The USB1 protein is characterized by two tetrapeptide motifs (HLSL), containing histidine and serine residues (H120, S122, and H208, S210) which are essential for its catalytic activity. Recognition of these motifs by computational analysis of the protein sequence has predicted USB1 belongs to the 2H phosphodiesterase superfamily present in bacteria, archea and eukaryotes (Colombo et al., 2012). The protein has a globular architecture with two juxtaposed lobes with a pseudo two-fold symmetry separated by a central groove, which exposes the two HLSL motifs of the active site (Fig.3).
|Expression|| USB1 is ubiquitously expressed in humans (Volpi et al., 2010).The high evolutionary conservation of the protein is consistent with the housekeeping function of the gene.|
|Localisation|| A nuclear localization of USB1 has been demonstrated in HeLa cells (Mroczek et al., 2012); both nuclear and mitochondrial localizations have been observed for the yeast orthologue (Glatigny et al., 2011).|
|Function|| Usb1 is a 3'-5' RNA exoribonuclease that trims the 3' end of the U6 snRNA leading to the formation of a terminal 2',3' cyclic phosphate. This post-transcriptionally modification influences U6 stability and recycling. Evidence has been obtained in yeast where Usb1 depletion leads to reduced levels of U6, generalized pre-mRNA splicing defects and shorter telomeres. In human use of PN cell lines confirmed that U6 is a substrate of USB1, but failed to reveal a splicing defect leaving unsolved how PN develops (Hilcenko et al., 2012; Mroczek et al., 2012; Shchepachev et al., 2012).|
| || |
|Entity|| Poikiloderma with neutropenia syndrome (PN)|
|Note|| The disease is caused by mutations affecting the gene represented in this entry. |
The clinical presentation of PN patients partially overlaps that of patients affected with Rothmund-Thomson syndrome (RTS; OMIM#268400) and dyskeratosis congenita (DC; OMIM#613987, #613988, #613989, #615190, #224230).
|Disease|| Poikiloderma with neutropenia is a rare inherited genodermatosis characterized by skin alterations (poikiloderma, nail dystrophy, palmo-plantar hyperkeratosis), short stature and non cyclic neutropenia. |
In infancy, neutropenia is responsible of the recurrent infections, mainly of the respiratory system, observed in PN patients and, later in life, may lead to myelodysplastic syndrome and acute myeloid leukaemia. Squamous cell carcinoma has also been reported in PN patients.
To date, 38 out of 66 PN patients described in literature have been molecularly tested and found to carry biallelic mutations of the USB1 gene. Most of the reported patients carry homozygous mutations, attesting inheritance by descent of the same ancestral mutation.
|Prognosis|| The knowledge of USB1 3D structure with the essential amino acid motifs of the catalytic site might enhance the prediction of USB1 mutation effects.|
All the mutations reported so far in PN patients (no. 19) interfere with USB1 function: 16 disrupt the catalytic activity due to the loss of one or both HLSL motifs, while the remaining 3 mutations, although not affecting the catalytically active tetrapeptide motifs destroy the internal symmetry of the protein. Owing to the restricted number of molecularly characterised PN patients no mutation-phenotype correlations have emerged suitable to stratify the patients according to life-long cancer risk (myelodysplasia and solid tumours).
Further studies focussing on the alternative transcript are necessary to establish the role of isoform 4 on PN pathogenesis and prognosis.
| || |
| Poikiloderma with neutropenia: a novel C16orf57 mutation and clinical diagnostic criteria.|
| Arnold AW, Itin PH, Pigors M, Kohlhase J, Bruckner-Tuderman L, Has C.|
| Br J Dermatol. 2010 Oct;163(4):866-9. doi: 10.1111/j.1365-2133.2010.09929.x. Epub 2010 Sep 7.|
| Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations.|
| Colombo EA, Bazan JF, Negri G, Gervasini C, Elcioglu NH, Yucelten D, Altunay I, Cetincelik U, Teti A, Del Fattore A, Luciani M, Sullivan SK, Yan AC, Volpi L, Larizza L.|
| Orphanet J Rare Dis. 2012 Jan 23;7:7. doi: 10.1186/1750-1172-7-7.|
| An in silico approach combined with in vivo experiments enables the identification of a new protein whose overexpression can compensate for specific respiratory defects in Saccharomyces cerevisiae.|
| Glatigny A, Mathieu L, Herbert CJ, Dujardin G, Meunier B, Mucchielli-Giorgi MH.|
| BMC Syst Biol. 2011 Oct 25;5:173. doi: 10.1186/1752-0509-5-173.|
| Aberrant 3' oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia.|
| Hilcenko C, Simpson PJ, Finch AJ, Bowler FR, Churcher MJ, Jin L, Packman LC, Shlien A, Campbell P, Kirwan M, Dokal I, Warren AJ.|
| Blood. 2013 Feb 7;121(6):1028-38. doi: 10.1182/blood-2012-10-461491. Epub 2012 Nov 27.|
| C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3' end modification.|
| Mroczek S, Krwawicz J, Kutner J, Lazniewski M, Kucin'ski I, Ginalski K, Dziembowski A.|
| Genes Dev. 2012 Sep 1;26(17):1911-25. doi: 10.1101/gad.193169.112. Epub 2012 Aug 16.|
| Mpn1, mutated in poikiloderma with neutropenia protein 1, is a conserved 3'-to-5' RNA exonuclease processing U6 small nuclear RNA.|
| Shchepachev V, Wischnewski H, Missiaglia E, Soneson C, Azzalin CM.|
| Cell Rep. 2012 Oct 25;2(4):855-65. doi: 10.1016/j.celrep.2012.08.031. Epub 2012 Sep 27.|
| Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene.|
| Volpi L, Roversi G, Colombo EA, Leijsten N, Concolino D, Calabria A, Mencarelli MA, Fimiani M, Macciardi F, Pfundt R, Schoenmakers EF, Larizza L.|
| Am J Hum Genet. 2010 Jan;86(1):72-6. doi: 10.1016/j.ajhg.2009.11.014. Epub 2009 Dec 10.|