USB1

Summary

USB1 (U6 snRNA biogenesis phosphodiesterase 1, HGNC:25792) is a protein-coding gene on chromosome 16q21, encoding U6 snRNA phosphodiesterase 1 (Q9BQ65). 3’-5’ RNA exonuclease that trims the 3’ end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3’ end-terminated with a 2’,3’-cyclic phosphate.

This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 79650 — RefSeq curated summary.

At a glance

• Gene–disease (curated): poikiloderma with neutropenia (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 549 total — 20 pathogenic, 9 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 11 tissues, sQTL in 16 (q < 0.05)
• Phenotypes (HPO): 97
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.02 (unconstrained)
• MANE Select transcript: NM_024598

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25792
Approved symbol	USB1
Name	U6 snRNA biogenesis phosphodiesterase 1
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13154, HVSL1, Mpn1
Ensembl gene	ENSG00000103005
Ensembl biotype	protein_coding
OMIM	613276
Entrez	79650

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 protein_coding, 6 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 TEC

MANE Select: ENST00000219281

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 6, TSL 3: 1, TSL 4: 6, TSL 5: 1

ENST00000219281, ENST00000423271, ENST00000539737, ENST00000561568, ENST00000561743, ENST00000562534, ENST00000563149, ENST00000563207, ENST00000564387, ENST00000565151, ENST00000565662, ENST00000566082, ENST00000566292, ENST00000568848, ENST00000569252, ENST00000624720, ENST00000698444, ENST00000698445, ENST00000698446, ENST00000698447, ENST00000698510, ENST00000896281, ENST00001132677

RefSeq mRNA: 5 — MANE Select: NM_024598 NM_001195302, NM_001204911, NM_001330568, NM_001330569, NM_024598

CCDS: CCDS10791, CCDS55997, CCDS55998, CCDS81990, CCDS81991

Canonical transcript exons

ENST00000219281 — 7 exons

Exon	Start	End
ENSE00003462019	58014273	58014326
ENSE00003495565	58002479	58002645
ENSE00003562189	58018972	58019055
ENSE00003588036	58009929	58010112
ENSE00003654987	58017334	58017439
ENSE00003973836	58001407	58001581
ENSE00004781181	58020141	58021618

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 94.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.1700 / max 438.5849, expressed in 1818 samples.

Highest expression (Bgee): granulocyte, leukocyte, monocyte, mononuclear cell, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

USB1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 16 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 27 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	sqtl	4.0e-50	+0.72	16:57982916:G:C
Testis	sqtl	2.1e-27	+0.86	16:58011565:G:A
Thyroid	sqtl	1.8e-16	+0.74	16:57983935:C:G
Lung	sqtl	2.2e-16	+0.75	16:57983935:C:G
Esophagus Mucosa	sqtl	2.2e-12	-0.72	16:57983935:C:G
Skin Sun Exposed Lower leg	sqtl	6.2e-12	+0.63	16:57970275:C:T
Esophagus Muscularis	sqtl	1.2e-11	-0.46	16:57974738:G:A
Skin Not Sun Exposed Suprapubic	sqtl	2.8e-11	+0.63	16:57987491:A:C
Esophagus Gastroesophageal Junction	sqtl	6.8e-08	+0.47	16:57982916:G:C
Breast Mammary Tissue	sqtl	3.0e-06	-0.44	16:57987780:A:G
Pancreas	eqtl	2.7e-05	-0.28	16:57993073:G:A
Thyroid	eqtl	5.2e-05	+0.17	16:58031555:G:A
Colon Sigmoid	sqtl	7.9e-05	+0.56	16:57987780:A:G
Whole Blood	eqtl	1.5e-04	+0.08	16:57996288:A:C
Adipose Visceral Omentum	sqtl	1.8e-04	+0.44	16:57983935:C:G
Whole Blood	sqtl	3.1e-04	-0.23	16:57996288:A:C
Colon Transverse	sqtl	8.4e-04	+0.30	16:57982916:G:C
Prostate	sqtl	1.6e-03	-0.53	16:57983935:C:G
Esophagus Mucosa	eqtl	3.6e-03	-0.15	16:57990148:T:A
Breast Mammary Tissue	eqtl	4.0e-03	-0.38	16:58965448:C:G

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
154429	44.0151	1818
154428	0.9214	235
154427	0.2336	83

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.93	gold quality
leukocyte	CL:0000738	93.21	gold quality
monocyte	CL:0000576	93.17	gold quality
mononuclear cell	CL:0000842	93.08	gold quality
blood	UBERON:0000178	92.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.57	gold quality
lower esophagus	UBERON:0013473	91.54	gold quality
right adrenal gland	UBERON:0001233	91.50	gold quality
right adrenal gland cortex	UBERON:0035827	91.35	gold quality
left adrenal gland	UBERON:0001234	91.31	gold quality
left adrenal gland cortex	UBERON:0035825	90.96	gold quality
anterior cingulate cortex	UBERON:0009835	90.73	gold quality
cingulate cortex	UBERON:0003027	90.72	gold quality
islet of Langerhans	UBERON:0000006	90.64	gold quality
mucosa of transverse colon	UBERON:0004991	90.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.44	gold quality
right coronary artery	UBERON:0001625	90.42	gold quality
adrenal cortex	UBERON:0001235	90.25	gold quality
right lobe of thyroid gland	UBERON:0001119	90.21	gold quality
left lobe of thyroid gland	UBERON:0001120	90.19	gold quality
adrenal gland	UBERON:0002369	90.10	gold quality
heart left ventricle	UBERON:0002084	90.01	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.93	gold quality
stromal cell of endometrium	CL:0002255	89.88	gold quality
oocyte	CL:0000023	89.81	gold quality
apex of heart	UBERON:0002098	89.78	gold quality
cardiac ventricle	UBERON:0002082	89.61	gold quality
upper lobe of left lung	UBERON:0008952	89.43	gold quality
smooth muscle tissue	UBERON:0001135	89.36	gold quality
thoracic aorta	UBERON:0001515	89.30	gold quality
spleen	UBERON:0002106	89.26	gold quality
thyroid gland	UBERON:0002046	89.23	gold quality
ascending aorta	UBERON:0001496	89.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.17	gold quality
right atrium auricular region	UBERON:0006631	89.13	gold quality
right frontal lobe	UBERON:0002810	89.08	gold quality
right lobe of liver	UBERON:0001114	89.03	gold quality
cervix squamous epithelium	UBERON:0006922	88.97	silver quality
transverse colon	UBERON:0001157	88.95	gold quality
body of stomach	UBERON:0001161	88.95	gold quality
descending thoracic aorta	UBERON:0002345	88.82	gold quality
mucosa of stomach	UBERON:0001199	88.78	gold quality
left coronary artery	UBERON:0001626	88.73	gold quality
upper lobe of lung	UBERON:0008948	88.70	gold quality
left uterine tube	UBERON:0001303	88.67	gold quality
esophagus	UBERON:0001043	88.65	gold quality
aorta	UBERON:0000947	88.62	gold quality
metanephros cortex	UBERON:0010533	88.50	gold quality
coronary artery	UBERON:0001621	88.45	gold quality
right testis	UBERON:0004534	88.42	gold quality
rectum	UBERON:0001052	88.40	gold quality
vermiform appendix	UBERON:0001154	88.39	gold quality
cardiac atrium	UBERON:0002081	88.30	gold quality
right lung	UBERON:0002167	88.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.24	gold quality
left testis	UBERON:0004533	88.23	gold quality
popliteal artery	UBERON:0002250	88.22	gold quality
tibial artery	UBERON:0007610	88.21	gold quality
pancreas	UBERON:0001264	88.10	gold quality
cortical plate	UBERON:0005343	88.10	gold quality
heart	UBERON:0000948	88.05	gold quality
body of uterus	UBERON:0009853	87.88	gold quality
ectocervix	UBERON:0012249	87.79	gold quality
endocervix	UBERON:0000458	87.68	gold quality
amygdala	UBERON:0001876	87.63	gold quality
lymph node	UBERON:0000029	87.62	gold quality
prefrontal cortex	UBERON:0000451	87.60	gold quality
omental fat pad	UBERON:0010414	87.47	gold quality
body of pancreas	UBERON:0001150	87.46	gold quality
peritoneum	UBERON:0002358	87.44	gold quality
gall bladder	UBERON:0002110	87.30	gold quality
adenohypophysis	UBERON:0002196	87.23	gold quality
ganglionic eminence	UBERON:0004023	87.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.07	gold quality
small intestine	UBERON:0002108	86.98	gold quality
caudate nucleus	UBERON:0001873	86.88	gold quality
testis	UBERON:0000473	86.82	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.78	gold quality
putamen	UBERON:0001874	86.77	gold quality
stomach	UBERON:0000945	86.63	gold quality
hypothalamus	UBERON:0001898	86.62	gold quality
neocortex	UBERON:0001950	86.60	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.59	gold quality
caecum	UBERON:0001153	86.53	gold quality
nucleus accumbens	UBERON:0001882	86.45	gold quality
esophagus mucosa	UBERON:0002469	86.41	gold quality
minor salivary gland	UBERON:0001830	86.39	gold quality
lower esophagus mucosa	UBERON:0035834	86.38	gold quality
colon	UBERON:0001155	86.37	gold quality
large intestine	UBERON:0000059	85.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.95	gold quality
frontal cortex	UBERON:0001870	85.90	gold quality
intestine	UBERON:0000160	85.88	gold quality
uterine cervix	UBERON:0000002	85.76	gold quality
vagina	UBERON:0000996	85.75	gold quality
bone marrow cell	CL:0002092	85.71	gold quality
gastrocnemius	UBERON:0001388	85.64	gold quality
colonic epithelium	UBERON:0000397	85.44	gold quality
pituitary gland	UBERON:0000007	85.31	gold quality
saliva-secreting gland	UBERON:0001044	85.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	30.1	low
Urinary bladder	tissue	26.0	not detected
Appendix	tissue	25.7	not detected
Smooth muscle	tissue	22.9	medium
Postcentral gyrus	tissue	22.3
Tonsil	tissue	19.8	not detected
Heart muscle	tissue	19.7	not detected
Adipose tissue	tissue	19.7	medium
Locus coeruleus	tissue	19.4
Lymph node	tissue	18.4	not detected
Rectum	tissue	17.9	medium
Thyroid gland	tissue	17.4	medium
Seminal vesicle	tissue	17.1	not detected
Adrenal gland	tissue	17.1	medium
Thymus	tissue	17.0
Lung	tissue	16.8	low
Hippocampus	tissue	16.6	low
Epididymis	tissue	16.1	not detected
Colon	tissue	15.8	medium
Placenta	tissue	15.3	not detected
Vagina	tissue	15.1	not detected
Liver	tissue	15.0	low
Spleen	tissue	14.9	not detected
Esophagus	tissue	14.2	not detected
Parathyroid gland	tissue	14.0	not detected
Cervix	tissue	13.8	low
Skin 1	tissue	13.7	low
Stomach 1	tissue	13.6	not detected
Gallbladder	tissue	13.6	medium
Pituitary gland	tissue	13.3
Testis	tissue	13.1	not detected
Nucleus accumbens	tissue	13.1
Prostate	tissue	12.7	not detected
Small intestine	tissue	12.2	medium
Pancreas	tissue	12.1	low
Duodenum	tissue	12.1	medium
Choroid plexus	tissue	11.9
Endometrium 1	tissue	11.7	not detected
Tongue	tissue	11.6
Fallopian tube	tissue	10.7	low
Salivary gland	tissue	10.4	not detected
Kidney	tissue	9.9	medium
Breast	tissue	9.6	low
Ovary	tissue	9.3	low
Superior colliculi	tissue	7.5
Spinal cord	tissue	7.5
Caudate putamen	tissue	7.4
Frontal cortex	tissue	7.3
Thalamus	tissue	7.1
Pons	tissue	7.0
Medulla oblongata	tissue	6.9
Substantia nigra	tissue	6.9
Midbrain	tissue	6.7
Hippocampal formation	tissue	6.5
Cerebral cortex	tissue	6.4	medium
Retina	tissue	6.4
Motor cortex	tissue	6.4
Somatosensory cortex	tissue	6.4
Prefrontal cortex	tissue	6.3
Putamen	tissue	6.3

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Nucleus ambiguus (24.7), Nuclei of the trapezoid body (22.6), Arcuate nucleus (22.2), Anterior thalamic nucleus, ventral (21.9), Nucleus raphe magnus (21.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting USB1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 111 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Functional genomics

gnomAD constraint: pLI 3.14e-05, LOEUF 1.02, missense Z 0.582 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000219281 — one region, missense o/e 0.95. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 25)

• c16orf57 has a role in clericuzio-type poikiloderma with neutropenia (PMID:20004881)
• report on detailed clinical features of three siblings affected with Clericuzio poikiloderma with neutropenia syndrome, all carrying the same homozygous c.504-2A>Cmutation at the acceptor splice site of intron 4 of C16orf57 gene (PMID:20734427)
• findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. (PMID:20817924)
• Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia. (PMID:21271650)
• Mutations of the C16orf57 gene permit the unification of a distinct group of genetic polikilodermal dermatoses that can be diagnosed as congenital dyskeratosis, Rothmund-Thomson syndrome, poikiloderma-neutropenia. (PMID:21497268)
• We report three cases of poikiloderma with neutropenia whose clinical presentations, laboratory investigations, and C16orf57 mutation support the diagnosis. (PMID:21967010)
• characterization of 6 Poikiloderma with Neutropenia patients and mutational repertoire of the gene; detected 2 novel C16orf57 mutations, c.232C>T and c.265 2T>G and the reported c.179delC, c.531delA and c.693 1G>T mutations; bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function (PMID:22269211)
• Advanced bioinformatics predicted that C16orf57 encodes a phosphodiesterase whose putative catalytic activity is essential for its function in vivo (PMID:22899009)
• Recombinant hMpn1 is a 3’-to-5’ RNA exonuclease that removes uridines from U6 3’ ends, generating terminal 2’,3’ cyclic phosphates in vitro. (PMID:23022480)
• Data indicate that USB1 measures the appropriate length of the U6 oligo(U) tail by reading the position of a key adenine nucleotide (A102) and pausing 5 uridine residues downstream. (PMID:23190533)
• Mpn1 associates with the NineTeen Complex, a multiprotein complex that is essential for the maintenance of spliceosome integrity and efficient splicing. [Review] (PMID:23684637)
• the link between Mpn1 and snRNA stability (PMID:26213367)
• USB1 genes from myelodysplastic and myelodysplastic/myeloproliferative neoplasms and AML had 3 unreported variants, 2 in USB1 5’UTR (c.-83G>T and c.-66A>G), 1 in IVS3 (c.450-68dupT) and 1 (<1%) in IVS4 (c.587+21A>G/rs200924980) were detected. (PMID:26306619)
• marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements. (PMID:27612988)
• this paper describes USB1 mutations characterized in four Moroccan patients out of three unrelated consanguinous families (PMID:28353165)
• Data indicate the enzymatic activities and structures of yeast and human U6 RNA processing enzyme Usb1. (PMID:28887445)
• A novel homozygous deletion of a 1-bp (c.161delC, p.P54RfsX60) in the C16orf57gene, was presumed to be causative of poikiloderma with neutropenia. The patient’s asymptomatic consanguineous parents were heterozygotes for this mutation. (PMID:29797650)
• Data show that U6 snRNA phosphodiesterase (Usb1) removes 3’ adenosines with 20-fold greater efficiency than uridines. (PMID:30215753)
• Here we investigate the molecular basis for the evolution of Usb1 CPDase activity. We examine the structure and function of Usb1 from Kluyveromyces marxianus, which shares 25 and 19% sequence identity to the S. cerevisiae and Homo sapiens orthologs of Usb1, respectively (PMID:31832688)
• Clinical Sequencing Solves a Diagnostic Dilemma by Identifying a Novel Pathogenic Variant in USB1 Gene Causing Poikiloderma with Neutropenia. (PMID:32936385)
• Clericuzio-type poikiloderma with neutropenia in a patient from India. (PMID:33111394)
• Kindler epidermolysis bullosa-like skin phenotype and downregulated basement membrane zone gene expression in poikiloderma with neutropenia and a homozygous USB1 mutation. (PMID:34004352)
• USB1 is a miRNA deadenylase that regulates hematopoietic development. (PMID:36862787)
• Chinese nontwin sisters suffer from poikiloderma with neutropenia harboring novel compound heterozygous USB1 gene mutations. (PMID:36938655)
• Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type. (PMID:37779259)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	usb1	ENSDARG00000003841
mus_musculus	Usb1	ENSMUSG00000031792
rattus_norvegicus	Usb1	ENSRNOG00000013216
drosophila_melanogaster	CG16790	FBGN0037713

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2142454) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal forebrain morphology	1
incomplete embryo turning	1
abnormal placenta development	1
abnormal placenta labyrinth morphology	1
edema	1
hemorrhage	1
abnormal tail morphology	1
abnormal pharyngeal arch morphology	1
embryonic growth retardation	1
abnormal trophoblast layer morphology	1
embryonic lethality during organogenesis, complete penetrance	1
preweaning lethality, complete penetrance	1
abnormal head shape	1
embryonic lethality prior to tooth bud stage	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q0II50	83.8%	Diamond
Xenopus laevis	Q7ZYI9	54.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CSNK2A2	protein-coding	1459
CFAP20	protein-coding	29105
MMP15	protein-coding	4324
ZNF319	protein-coding	57567
SPMIP8	protein-coding	374739
KIFC3	protein-coding	3801
CNGB1	protein-coding	1258

Protein

Protein identifiers

U6 snRNA phosphodiesterase 1 — Q9BQ65 (reviewed: Q9BQ65)

Alternative names: 3’-5’ RNA exonuclease USB1, Mutated in poikiloderma with neutropenia protein 1

All UniProt accessions (11): Q9BQ65, A0A8V8TLQ0, A0A8V8TLS7, A0A8V8TM89, A0A8V8TM93, A0A8V8TN78, A0A8V8TNL4, H3BN52, H3BNM8, H3BTS1, H3BTT8

UniProt curated annotations — full annotation on UniProt →

Function. 3’-5’ RNA exonuclease that trims the 3’ end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3’ end-terminated with a 2’,3’-cyclic phosphate. Participates in the U6 snRNA 3’ end processing that prevents U6 snRNA degradation. In addition also removes uridines from the 3’ end of U6atac snRNA and possibly the vault RNA VTRNA1-1.

Subunit / interactions. Interacts with PLRG1, CDC5L and PRPF19.

Subcellular location. Nucleus.

Disease relevance. Poikiloderma with neutropenia (PN) [MIM:604173] A genodermatosis characterized by poikiloderma, pachyonychia and chronic neutropenia. The disorder starts as a papular erythematous rash on the limbs during the first year of life. It gradually spreads centripetally and, as the papular rash resolves, hypo- and hyperpigmentation result, with development of telangiectasias. Another skin manifestation is pachyonychia, but alopecia and leukoplakia are distinctively absent. Patients have recurrent pneumonias that usually result in reactive airway disease and/or chronic cough. One of the most important extracutaneous symptoms is an increased susceptibility to infections, mainly affecting the respiratory system, primarily due to a chronic neutropenia and to neutrophil functional defects. Bone marrow abnormalities account for neutropenia and may evolve into myelodysplasia associated with the risk of leukemic transformation. Poikiloderma with neutropenia shows phenotypic overlap with Rothmund-Thomson syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. 3’-5’ RNA exonuclease activity is inhibited by a 3’ phosphate terminated RNA.

Similarity. Belongs to the 2H phosphoesterase superfamily. USB1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BQ65-1	1	yes
Q9BQ65-2	2
Q9BQ65-3	3

RefSeq proteins (5): NP_001182231, NP_001191840, NP_001317497, NP_001317498, NP_078874* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027521	Usb1	Family

Pfam: PF09749

Catalyzed reactions (Rhea)

• a 3’-end uridylyl-uridine-RNA = a 3’-end 2’,3’-cyclophospho-uridine-RNA + uridine (RHEA:46052)
• a 3’-end uridylyl-adenosine-RNA = a 3’-end 2’,3’-cyclophospho-uridine-RNA + adenosine (RHEA:67896)

UniProt features (43 total): strand 9, helix 9, mutagenesis site 8, binding site 6, splice variant 2, sequence variant 2, sequence conflict 2, active site 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
4H7W	Crystal Structure of Human C16orf57	X-RAY DIFFRACTION	1.1
6D30	Structure of human Usb1 with uridine-uridine, inactive H208Q mutant	X-RAY DIFFRACTION	1.17
6D2Z	Structure of human Usb1 with uridine-adenosine, inactive H208Q mutant	X-RAY DIFFRACTION	1.18
6D31	Structure of human Usb1 with adenosine 5’-monophosphate	X-RAY DIFFRACTION	1.2
5V1M	Structure of human Usb1 with uridine 5’-monophosphate	X-RAY DIFFRACTION	1.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQ65-F1	83.91	0.65

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2)

Position	Role
120	proton acceptor
208	proton donor

Ligand- & substrate-binding residues (6)

Position	Role
206–210	UMP
120–122	AMP
164	UMP
202	AMP
202	UMP
204–210	AMP

Mutagenesis-validated functional residues (8)

Position	Phenotype
120	abolishes exoribonuclease activity. does not restore u6 snrna processing when expressed in deleted mpn1 yeast cells; when associated with …
120	significantly decreases exonuclease activity.
122	significantly decreases exonuclease activity.
202	significantly decreases exonuclease activity.
208	abolishes exoribonuclease activity. does not rescue the molecular phenotype caused by usb1 depletion. does not restore u6 snrna processing …
208	loss of exonuclease activity.
210	significantly decreases exonuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 354 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOMF_NUCLEASE_ACTIVITY, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_RNA_SPLICING, AACTTT_UNKNOWN, chr16q21, GOMF_EXONUCLEASE_ACTIVITY, ACEVEDO_LIVER_CANCER_UP, GOBP_SNRNA_PROCESSING, CHIBA_RESPONSE_TO_TSA, NUYTTEN_EZH2_TARGETS_DN, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, E2A_Q2

GO Biological Process (3): RNA splicing (GO:0008380), snRNA 3’-end processing (GO:0034472), U6 snRNA 3’-end processing (GO:0034477)

GO Molecular Function (6): 3’-5’-RNA exonuclease activity (GO:0000175), lyase activity (GO:0016829), poly(U)-specific exoribonuclease activity, producing 3’ uridine cyclic phosphate ends (GO:1990838), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

13 GO namespaces:

Category	Terms
catalytic activity	2
RNA processing	1
snRNA processing	1
RNA 3’-end processing	1
snRNA 3’-end processing	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
3’-5’-RNA exonuclease activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
RNA splicing	BP	mutant phenotype
U6 snRNA 3’-end processing	BP	direct assay
snRNA 3’-end processing	BP	mutant phenotype
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
3’-5’-RNA exonuclease activity	MF	direct assay
poly(U)-specific exoribonuclease activity, producing 3’ uridine cyclic phosphate ends	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 502 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USB1	RECQL4	O94761	901
USB1	LSM8	O95777	627
USB1	NOP10	Q9NPE3	625
USB1	PRSS38	A1L453	606
USB1	NHP2	Q9NX24	604
USB1	WRAP53	Q9BUR4	602
USB1	TINF2	Q9BSI4	585
USB1	TUT1	Q9H6E5	585
USB1	CTC1	Q2NKJ3	576
USB1	DKC1	O60832	556
USB1	PARN	O95453	532
USB1	SART3	Q15020	513
USB1	RTEL1	Q9NZ71	509
USB1	DIS3L2	Q8IYB7	504
USB1	ARMC7	Q9H6L4	476

IntAct

Human interaction partners of USB1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
AQR	association	0.530	1
ECE1	physical association	0.370	1
SMAD4	physical association	0.370	1
PLRG1	association	0.350	2
IGLL5	association	0.350	1

BioGRID (96 interactions; top human partners by supporting records): CDC5L (Affinity Capture-MS; 5 records), PLRG1 (Affinity Capture-MS; 5 records), PRPF19 (Affinity Capture-MS; 5 records), AQR (Affinity Capture-MS; 3 records), BCAS2 (Affinity Capture-MS; 3 records), CCDC12 (Affinity Capture-MS; 3 records), CDC40 (Affinity Capture-MS; 3 records), CRNKL1 (Affinity Capture-MS; 3 records), CWF19L2 (Affinity Capture-MS; 3 records), DHX35 (Affinity Capture-MS; 3 records), GPATCH1 (Affinity Capture-MS; 3 records), ISY1 (Affinity Capture-MS; 3 records), PPIE (Affinity Capture-MS; 3 records), RBM22 (Affinity Capture-MS; 3 records), SNW1 (Affinity Capture-MS; 3 records)

Disease & clinical

Genetic variants

Variant evidence for USB1: 549 ClinVar records (29 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

549 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	9
Uncertain significance	292
Likely benign	184
Benign	17

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 29 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
496754	NM_024598.4(USB1):c.266-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	4
496747	NM_024598.4(USB1):c.623A>G (p.His208Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
496744	NM_024598.4(USB1):c.499del (p.Thr167fs)	Pathogenic	criteria provided, single submitter	3
496761	NM_024598.4(USB1):c.489_492del (p.Asn163fs)	Pathogenic	criteria provided, single submitter	3
496748	NM_024598.4(USB1):c.673C>T (p.Gln225Ter)	Pathogenic	criteria provided, single submitter	2
496749	NM_024598.4(USB1):c.693+1G>T	Pathogenic	criteria provided, single submitter	2
496750	NM_024598.4(USB1):c.176_177del (p.Gly59fs)	Pathogenic	criteria provided, single submitter	2
496757	NM_024598.4(USB1):c.415C>T (p.Gln139Ter)	Pathogenic	criteria provided, single submitter	2
1338346	NM_024598.4(USB1):c.481del (p.Tyr161fs)	Pathogenic	criteria provided, single submitter	1
1338579	NM_024598.4(USB1):c.206del (p.Gly69fs)	Pathogenic	criteria provided, single submitter	1
1924645	NM_024598.4(USB1):c.430del (p.Arg144fs)	Pathogenic	criteria provided, single submitter	1
1941491	NM_024598.4(USB1):c.267T>G (p.Tyr89Ter)	Pathogenic	criteria provided, single submitter	1
4729837	NM_024598.4(USB1):c.193del (p.Thr65fs)	Pathogenic	criteria provided, single submitter	1
559873	NM_024598.4(USB1):c.345del (p.Arg115_Met116insTer)	Likely pathogenic	criteria provided, single submitter	1
1066183	NM_024598.4(USB1):c.418_449+5del	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore USB1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 774):

Position(s)	Effect	Δscore	Sites
16:58001530	donor_gain	1.0000
16:58002477–58002478	acceptor_loss	1.0000	6
16:58012817	donor_gain	1.0000
16:58017332–58017333	acceptor_loss	1.0000	6
16:58017440–58017441	donor_loss	1.0000	2
16:58001594	donor_gain	0.9900
16:58002474	acceptor_gain	0.9900
16:58002617	donor_gain	0.9900
16:58002646–58002647	donor_loss	0.9900	5
16:58011126	donor_gain	0.9900

AlphaMissense

441 missense substitutions predicted likely pathogenic (of 1,753 scored), across 122 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F170	8	0.938	0.994
H208	8	0.923	0.987
S122	8	0.870	0.991
H120	8	0.862	0.969
H76	8	0.822	0.966
W81	7	0.967	0.986
F196	7	0.932	0.988
S210	7	0.927	0.992
F201	7	0.922	0.982
F207	7	0.916	0.979
N163	7	0.901	0.975
R168	7	0.875	0.968
D190	7	0.862	0.921
F74	7	0.848	0.979
F53	7	0.793	0.942
F137	7	0.775	0.911
H132	7	0.731	0.831
H67	7	0.714	0.848
W133	7	0.712	0.875
D217	7	0.602	0.691

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	6.55e-07

Disease associations

OMIM: gene MIM:613276 | disease phenotypes: MIM:604173

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
poikiloderma with neutropenia	Definitive	Autosomal recessive	4
dyskeratosis congenita	Supportive	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
COVID-19 research	green
Cytopenia - NOT Fanconi anaemia	green
DDG2P	green
Paediatric disorders	green
Pigmentary skin disorders	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (2): poikiloderma with neutropenia (MONDO:0011405), dyskeratosis congenita (MONDO:0015780)

Orphanet (1): Poikiloderma with neutropenia (Orphanet:221046)

HPO phenotypes

showing 60 of 97 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000035	Abnormal testis morphology
HP:0000164	Abnormality of the dentition
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000430	Underdeveloped nasal alae
HP:0000498	Blepharitis
HP:0000499	Abnormal eyelash morphology
HP:0000509	Conjunctivitis
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000579	Nasolacrimal duct obstruction
HP:0000600	Abnormality of the pharynx
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000704	Periodontitis
HP:0000819	Diabetes mellitus
HP:0000939	Osteoporosis
HP:0000962	Hyperkeratosis
HP:0000969	Edema
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash
HP:0001009	Telangiectasia
HP:0001029	Poikiloderma
HP:0001034	Hypermelanotic macule
HP:0001053	Hypopigmented skin patches
HP:0001231	Abnormal fingernail morphology
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0001387	Joint stiffness
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001874	Abnormality of neutrophils
HP:0001875	Decreased total neutrophil count
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001928	Abnormality of coagulation
HP:0002007	Frontal bossing
HP:0002024	Malabsorption
HP:0002162	Low posterior hairline
HP:0002205	Recurrent respiratory infections
HP:0002216	Premature graying of hair
HP:0002240	Hepatomegaly
HP:0002514	Cerebral calcification
HP:0002575	Tracheoesophageal fistula
HP:0002650	Scoliosis
HP:0002664	Neoplasm

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
2-palmitoylglycerol	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Diazinon	increases methylation	1
Diuron	decreases expression	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tunicamycin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4VQ	PN1-iPSC	Induced pluripotent stem cell	Female
CVCL_A4VR	PN2-iPSC	Induced pluripotent stem cell	Female
CVCL_B2KG	Abcam HeLa USB1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

19 trials:

NCT	Phase	Status	Title
NCT00004787	Phase 2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01659606	Phase 2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	Phase 2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	Phase 2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04638517	Phase 2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT01917708	Phase 1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT06477614	Phase 1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	Phase 1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT07628972	Phase 1	RECRUITING	Quercetin Dyskeratosis Congenita (DC)/Telomere Biology Disorders (TBD)
NCT00455312	Phase 2/3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01001598	Phase 1/2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02162420	Not specified	COMPLETED	Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT04959188	Not specified	COMPLETED	Needs Assessment for Individuals and Families Affected by Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders (TBD)
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts