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USB1 (U6 snRNA biogenesis 1)

Written2014-02Elisa Adele Colombo
Genetica Medica, Dipartimento di Scienze della Salute, Universita degli Studi di Milano, Italy

Abstract C16orf57 alias USB1 is the gene which mutations underlie poikiloderma with neutropenia (PN) syndrome, a rare genodermatosis with autosomic recessive inheritance. PN patients have an increased risk to develop myelodysplasia and acute myeloid leukaemia in the second decade of life. In 2012, the protein encoded by USB1 has been recognised to be a 2H phosphodiesterase involved in the processing of U6 snRNA, but its action pathway and hence role in the pathogenesis of PN has not yet been elucidated.

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Identity

Alias_namesC16orf57
chromosome 16 open reading frame 57
U6 snRNA biogenesis 1
Alias_symbol (synonym)FLJ13154
HVSL1
Mpn1
Other aliasEC 3.1.4.
hUsb1
PN
HGNC (Hugo) USB1
LocusID (NCBI) 79650
Atlas_Id 44608
Location 16q21  [Link to chromosome band 16q21]
Location_base_pair Starts at 58001373 and ends at 58021623 bp from pter ( according to hg19-Feb_2009)  [Mapping USB1.png]
 
  Figure 1. The region on chromosome 16q21 containing USB1 and its neighbouring genes ZNF139 (zinc finger protein 319) and MMP15 (matrix metalloproteinase 15) (UCSC database -GRCh37/hg19, Feb 2009).
Fusion genes
(updated 2016)
USB1 (16q21) / DRC7 (16q21)

DNA/RNA

 
  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.

Protein

 
  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).

Mutations

 
  Figure 4. Map across the USB1 gene of the currently known 19 mutations. Nonsense mutations are represented with a red hexagon, deletions with a yellow star and splicing mutations with a blue triangle. The Table lists for each mutation the intragenic position, the description (cDNA nomenclature) and the effect at the protein level.
Germinal Biallelic mutations in USB1 gene (OMIM*613276) cause poikiloderma with neutropenia syndrome (OMIM#604173).
To date, 19 different "loss-of-function" mutations have been identified in 38 molecularly tested PN patients: 7 non-sense mutations, 6 out-of-frame deletions and 6 canonical splice site mutations. The latter also include the only missense mutation so far reported which however leads to exon skipping (Volpi et al., 2010). Recurrent mutations can be identified in patients of Navajo, Turkish and Caucasian origin attesting a founder effect (Colombo et al., 2012).
Somatic No information is currently available on mutations of USB1 in sporadic cancers.

Implicated in

Note
  
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.
  

Bibliography

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.
PMID 20618321
 
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.
PMID 22269211
 
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.
PMID 22027258
 
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.
PMID 23190533
 
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.
PMID 22899009
 
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.
PMID 23022480
 
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.
PMID 20004881
 

Citation

This paper should be referenced as such :
EA Colombo
USB1 (U6 snRNA biogenesis 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(9):678-681.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/USB1ID44608ch16q21.html


External links

Nomenclature
HGNC (Hugo)USB1   25792
LRG (Locus Reference Genomic)LRG_352
Cards
AtlasUSB1ID44608ch16q21
Entrez_Gene (NCBI)USB1  79650  U6 snRNA biogenesis phosphodiesterase 1
AliasesC16orf57; HVSL1; Mpn1; PN; 
hUsb1
GeneCards (Weizmann)USB1
Ensembl hg19 (Hinxton)ENSG00000103005 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000103005 [Gene_View]  chr16:58001373-58021623 [Contig_View]  USB1 [Vega]
ICGC DataPortalENSG00000103005
TCGA cBioPortalUSB1
AceView (NCBI)USB1
Genatlas (Paris)USB1
WikiGenes79650
SOURCE (Princeton)USB1
Genetics Home Reference (NIH)USB1
Genomic and cartography
GoldenPath hg38 (UCSC)USB1  -     chr16:58001373-58021623 +  16q21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)USB1  -     16q21   [Description]    (hg19-Feb_2009)
EnsemblUSB1 - 16q21 [CytoView hg19]  USB1 - 16q21 [CytoView hg38]
Mapping of homologs : NCBIUSB1 [Mapview hg19]  USB1 [Mapview hg38]
OMIM604173   613276   
Gene and transcription
Genbank (Entrez)AK023216 AK124443 AK126223 AK293220 AK298473
RefSeq transcript (Entrez)NM_001195302 NM_001204911 NM_001330568 NM_001330569 NM_024598
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)USB1
Cluster EST : UnigeneHs.408702 [ NCBI ]
CGAP (NCI)Hs.408702
Alternative Splicing GalleryENSG00000103005
Gene ExpressionUSB1 [ NCBI-GEO ]   USB1 [ EBI - ARRAY_EXPRESS ]   USB1 [ SEEK ]   USB1 [ MEM ]
Gene Expression Viewer (FireBrowse)USB1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)79650
GTEX Portal (Tissue expression)USB1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9BQ65   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9BQ65  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9BQ65
Splice isoforms : SwissVarQ9BQ65
PhosPhoSitePlusQ9BQ65
Domains : Interpro (EBI)Usb1   
Domain families : Pfam (Sanger)HVSL (PF09749)   
Domain families : Pfam (NCBI)pfam09749   
Conserved Domain (NCBI)USB1
DMDM Disease mutations79650
Blocks (Seattle)USB1
PDB (SRS)4H7W   
PDB (PDBSum)4H7W   
PDB (IMB)4H7W   
PDB (RSDB)4H7W   
Structural Biology KnowledgeBase4H7W   
SCOP (Structural Classification of Proteins)4H7W   
CATH (Classification of proteins structures)4H7W   
SuperfamilyQ9BQ65
Human Protein AtlasENSG00000103005
Peptide AtlasQ9BQ65
HPRD07815
IPIIPI00304431   IPI01015651   IPI00641878   IPI01008741   
Protein Interaction databases
DIP (DOE-UCLA)Q9BQ65
IntAct (EBI)Q9BQ65
FunCoupENSG00000103005
BioGRIDUSB1
STRING (EMBL)USB1
ZODIACUSB1
Ontologies - Pathways
QuickGOQ9BQ65
Ontology : AmiGO3'-5'-exoribonuclease activity  nucleus  mRNA processing  RNA splicing  U6 snRNA 3'-end processing  intercellular bridge  RNA phosphodiester bond hydrolysis, exonucleolytic  
Ontology : EGO-EBI3'-5'-exoribonuclease activity  nucleus  mRNA processing  RNA splicing  U6 snRNA 3'-end processing  intercellular bridge  RNA phosphodiester bond hydrolysis, exonucleolytic  
NDEx NetworkUSB1
Atlas of Cancer Signalling NetworkUSB1
Wikipedia pathwaysUSB1
Orthology - Evolution
OrthoDB79650
GeneTree (enSembl)ENSG00000103005
Phylogenetic Trees/Animal Genes : TreeFamUSB1
HOVERGENQ9BQ65
HOGENOMQ9BQ65
Homologs : HomoloGeneUSB1
Homology/Alignments : Family Browser (UCSC)USB1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerUSB1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)USB1
dbVarUSB1
ClinVarUSB1
1000_GenomesUSB1 
Exome Variant ServerUSB1
ExAC (Exome Aggregation Consortium)USB1 (select the gene name)
Genetic variants : HAPMAP79650
Genomic Variants (DGV)USB1 [DGVbeta]
DECIPHERUSB1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisUSB1 
Mutations
ICGC Data PortalUSB1 
TCGA Data PortalUSB1 
Broad Tumor PortalUSB1
OASIS PortalUSB1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICUSB1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDUSB1
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch USB1
DgiDB (Drug Gene Interaction Database)USB1
DoCM (Curated mutations)USB1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)USB1 (select a term)
intoGenUSB1
NCG5 (London)USB1
Cancer3DUSB1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM604173    613276   
Orphanet477    18933   
MedgenUSB1
Genetic Testing Registry USB1
NextProtQ9BQ65 [Medical]
TSGene79650
GENETestsUSB1
Target ValidationUSB1
Huge Navigator USB1 [HugePedia]
snp3D : Map Gene to Disease79650
BioCentury BCIQUSB1
ClinGenUSB1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD79650
Chemical/Pharm GKB GenePA143485394
Clinical trialUSB1
Miscellaneous
canSAR (ICR)USB1 (select the gene name)
Probes
Litterature
PubMed25 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineUSB1
EVEXUSB1
GoPubMedUSB1
iHOPUSB1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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