Alternative titles; symbols
HGNC Approved Gene Symbol: USB1
SNOMEDCT: 772126000;
Cytogenetic location: 16q21 Genomic coordinates (GRCh38) : 16:57,999,603-58,021,618 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q21 | Poikiloderma with neutropenia | 604173 | Autosomal recessive | 3 |
U6 small nuclear RNA (snRNA) (see 180692) is posttranscriptionally oligouridynylated by TUT1 (610641), and the last nucleotide of approximately 90% of U6 snRNA is modified to form a terminal 2-prime,3-prime-cyclic phosphate that is required for stability. USB1 is a phosphodiesterase responsible for U6 snRNA 3-prime end modification (Mroczek et al., 2012; Hilcenko et al., 2013).
By searching for genes in a region of chromosome 16 linked to Clericuzio-type poikiloderma with neutropenia (604173), Volpi et al. (2010) identified USB1, which they called C16ORF57. The deduced 265-amino acid protein contains 5 helical domains and is highly conserved among vertebrates. C16ORF57 was significantly expressed in myeloid lineage cells.
Mroczek et al. (2012) found that fluorescence-tagged human USB1 localized to nuclei of transfected HeLa cells.
Volpi et al. (2010) determined that the C16ORF57 gene contains 7 exons.
By genomic sequence analysis, Volpi et al. (2010) mapped the USB1 gene to chromosome 16q13.
Hartz (2017) mapped the USB1 gene to chromosome 16q21 based on an alignment of the USB1 sequence (GenBank AK023216) with the genomic sequence (GRCh38).
Using 3-dimensional homology modeling, Mroczek et al. (2012) determined that USB1 has 2 closely interacting and topologically equivalent repeats, or lobes, with a pseudo-2-fold rotational symmetry. Each lobe has a conserved HxT/S catalytic motif within a V-shaped active-site cleft.
Hilcenko et al. (2013) reported the crystal structure of human USB1 at 1.1-angstrom resolution.
Using a genetic screen, Mroczek et al. (2012) found that human USB1 complemented loss of Usb1 in yeast, with restored cell growth and splicing of a test pre-mRNA. Addition of U6 snRNA also partially rescued Usb1 deficiency in yeast. Knockdown of USB1 in HeLa cells via small interfering RNA did not alter U6 snRNA levels or significantly affect pre-mRNA splicing, but U6 snRNA molecules became extended with more heterogeneous length compared with controls due to TUT1 3-prime uridylation. Loss of USB1 also modestly decreased U6 snRNA stability. Human USB1 with mutation of his133 or his231 was unable to restore growth in Usb1-deficient yeast or USB1-knockdown HEK293 cells. Mroczek et al. (2012) concluded that USB1 catalyzes cleavage of the P-O(5-prime) bond at the 3-prime end of poly(U) in U6 snRNA, resulting in formation of a 2-prime,3-prime-cyclic phosphate and removal of the terminal uridine.
Hilcenko et al. (2013) found that mutation of the catalytic histidines or deletion of the N-terminal domain of human USB1 abrogated its ability to rescue Usb1 deletion in yeast. They showed that USB1 progressively trimmed 3-prime poly(A) as well as poly(U) in U6 snRNA and generated a 2-prime,3-prime-cyclic phosphate at the 3-prime end of U6 snRNA. USB1 read nucleotide A102 of U6 snRNA as a pause signal and stopped trimming 5 uridines downstream. In lymphoblasts from patients with poikiloderma with neutropenia (PN; 604173) due to USB1 mutation (see MOLECULAR GENETICS), Hilcenko et al. (2013) found that U6 snRNA had aberrant nontemplated 3-prime oligo(A) tails, which are characteristic of nuclear RNA surveillance targets. They concluded that USB1 functions in posttranscriptional 3-prime end processing that protects U6 snRNA from targeted destruction by the nuclear exosome.
In 3 affected sibs from a highly consanguineous Italian family with poikiloderma and neutropenia (PN; 604173), Volpi et al. (2010) identified homozygosity for a splice site mutation in the C16ORF57 gene (613276.0001). They also found compound heterozygosity for mutations in C16ORF57 (613276.0002-613276.0003) in an unrelated Italian female patient who had previously been reported by Pianigiani et al. (2001).
In a consanguineous Moroccan family with PN, Tanaka et al. (2010) identified a homozygous 1-bp deletion in the C16ORF57 gene (613276.0004) that segregated with the disorder.
In a proband and his cousin with PN, Arnold et al. (2010) identified a homozygous nonsense mutation in the C16ORF57 gene (W81X; 613276.0005). Both sets of parents were heterozygous for the mutation.
In 11 patients from 8 kindreds with PN, including 4 families of Athabaskan ancestry, Clericuzio et al. (2011) identified homozygous and compound heterozygous mutations in the C16ORF57 gene (see, e.g., 613276.0006-613276.0008). All patients in the Athabaskan families (Navajo or Apache) carried the same deletion (c.496delA; 613276.0006), suggesting that it represents a founder mutation.
In a patient with PN, Suter et al. (2016) identified homozygosity for a frameshift mutation in the USB1 gene (613276.0009). No functional studies were reported.
By sequencing of the USB1 gene in 3 unrelated patients with PN, Colombo et al. (2018) identified homozygous or compound heterozygous mutations in the USB1 gene (613276.0002; 613276.0005; 613276.0010-613276.0011).
In a Serbian patient with PN, Piccolo et al. (2021) identified homozygosity for the previously identified nonsense mutation (W81X; 613276.0011) in the USB1 gene. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
In 3 affected sibs from a highly consanguineous Italian family with poikiloderma and neutropenia (PN; 604173), Volpi et al. (2010) identified homozygosity for a 504-2A-C transversion at the splice acceptor site in intron 4 of the C16ORF57 gene. Subsequent cDNA analysis in an affected sib revealed an aberrant transcript that was 106 nucleotides shorter than normal due to skipping of exon 5.
In an Italian female patient with poikiloderma and neutropenia (PN; 604173), who had previously been reported by Pianigiani et al. (2001), Volpi et al. (2010) identified compound heterozygosity for a paternally inherited 12-bp deletion (683_693+1del12) in exon 6 of the C16ORF57 gene and a maternally inherited 502A-G transition in exon 4 at a highly conserved R168 residue (613276.0003) within the HVSL domain. The missense mutation was not found in 175 matched controls. Analysis of the patient's cDNA revealed 2 aberrant transcripts, with in-frame skipping of exons 6 (paternal allele) and 4 (maternal allele). Volpi et al. (2010) corrected the numbering of the 12-bp deletion from 666_675+1del12 to 683_693+1del12.
In a 6-year-old Italian boy (patient 49) with poikiloderma and neutropenia (PN; 604173), Colombo et al. (2018) identified homozygosity for the c.683_693+1del mutation (c.683_693+1del, NM_024598.2) in the USB1 gene. The mutation was identified by sequencing of the USB1 gene, and the parents were shown to be mutation carriers. Transcript analysis in patient lymphocytes demonstrated a single aberrant transcript lacking exon 6 of the USB1 gene, predicted to result in Asp204_Gln231del, leading to loss of the second His-Leu-Ser-Leu domain of the protein.
For discussion of the 502A-G transition in exon 4 of the C16ORF57 gene that was found in compound heterozygous state in a patient with poikiloderma and neutropenia (PN; 604173) by Volpi et al. (2010), see 613276.0002.
In 3 affected sibs from a consanguineous Moroccan family with poikiloderma and neutropenia (PN; 604173), previously studied by Mostefai et al. (2008), Tanaka et al. (2010) identified homozygosity for a 1-bp deletion (179delC) in the C16ORF57 gene, predicted to cause a frameshift and premature termination (Pro60fsTer54). The unaffected parents were heterozygous for the mutation, which was not found in an unaffected sister.
In an 8-year-old proband and his cousin with poikiloderma with neutropenia (PN; 604173), Arnold et al. (2010) identified a homozygous c.243G-A transition in the C16ORF57 gene, resulting in a trp81-to-ter (W81X; 613276.0005) substitution. Both sets of parents were heterozygous for the mutation. No functional studies were reported.
In a patient with PN, who had a diagnosis of Rothmund-Thomson syndrome (see 268400), Walne et al. (2010) identified homozygosity for the W81X mutation in the C16ORF57 gene.
In a 36-year-old Italian man (patient 48) with PN, Colombo et al. (2018) identified compound heterozygosity for 2 mutations in the USB1 gene: W81X and a c.541C-T transition in exon 5, resulting in a gln181-to-ter (Q181X; 613276.0011) substitution. The mutation was identified by USB1 gene sequencing, and the parents were shown to be mutation carriers. Transcript analysis in patient lymphocytes demonstrated that there were reduced transcripts from each USB1 allele, indicating partial escape from nonsense mediated decay, potentially leading to an aberrant truncated protein.
In 4 patients with poikiloderma with neutropenia (PN; 604173) from 3 families of Athabaskan descent, Clericuzio et al. (2011) identified homozygosity for a 1-bp deletion (c.496delA) in the C16ORF57 gene, resulting in a frameshift. In a patient of Athabaskan and Caucasian parents, Clericuzio et al. (2011) identified compound heterozygosity for the c.496delA mutation and a 4-bp deletion (c.489_492del4; 613276.0006). No functional studies were reported.
For discussion of the 4-bp deletion (c.489_492del4) in the C16ORF57 gene that was found in compound heterozygous state in a patient with poikiloderma with neutropenia (PN; 604173), see 613276.0005.
In affected members of 2 Asian Indian families with poikiloderma with neutropenia (PN; 604173), Clericuzio et al. (2011) identified homozygosity for a splice site mutation in intron 2 (c.266-1G-A) in the C16ORF57 gene. No functional studies were reported.
In a patient with poikiloderma with neutropenia (PN; 604173), Suter et al. (2016) identified homozygosity for a frameshift mutation in exon 3 of the USB1 gene (c.334_335dupC, NM_024598.3), resulting in a frameshift and premature termination (Arg112ProfsTer31). No functional studies were reported.
In a Turkish boy (patient 32) with poikiloderma with neutropenia (PN; 604173), Colombo et al. (2018) identified homozygosity for a 1-bp deletion (c.531delA, NM_024598.2) in exon 5 of the USB1 gene, predicted to result in a frameshift (His179fsTer86) with the same amino acid length as the wildtype protein but with a different composition of the last 85 residues at the C terminus. The mutation was identified by USB1 gene sequencing, and the parents were shown to be mutation carriers. The mutation was predicted to lead to loss of a tetrapeptide motif and affect the 2H active site.
For discussion of the c.541C-T transition (c.541C-T, NM_024598.2) in exon 5 of the USB1 gene, resulting in a gln181-to-ter (Q181X) substitution, that was found in compound heterozygous state in a patient with poikiloderma with neutropenia (PN; 604173) by Colombo et al. (2018), see 613276.0005.
In a Serbian patient with PN, Piccolo et al. (2021) identified homozygosity for W81X in the USB1 gene. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Arnold, A. W., Itin, P. H., Pigors, M., Kohlhase, J., Bruckner-Tuderman, L., Has, C. Poikiloderma with neutropenia: a novel C16orf57 mutation and clinical diagnostic criteria. Brit. J. Derm. 163: 866-869, 2010. [PubMed: 20618321] [Full Text: https://doi.org/10.1111/j.1365-2133.2010.09929.x]
Clericuzio, C., Harutyunyan, K., Jin, W., Erickson, R. P., Irvine, A. D., McLean, W. H. I., Wen, Y., Bagatell, R., Griffin, T. A., Shwayder, T. A., Plon, S. E., Wang, L. L. Identification of a novel C16ORF57 mutation in Athabaskan patients with poikiloderma with neutropenia. Am. J. Med. Genet. 155A: 337-342, 2011. [PubMed: 21271650] [Full Text: https://doi.org/10.1002/ajmg.a.33807]
Colombo, E. A., Elcioglu, N. H., Graziano, C., Farinelli, P., Di Fede, E., Neri, I., Facchini, E. Greco, M., Gervasini, C., Larizza, L. Insights into mutation effect in three poikiloderma with neutropenia patients by transcript analysis and disease evolution of reported patients with the same pathogenic variants. J. Clin. Immun. 38: 494-502, 2018. [PubMed: 29770900] [Full Text: https://doi.org/10.1007/s10875-018-0508-9]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/5/2017.
Hilcenko, C., Simpson, P. J., Finch, A. J., Bowler, F. R., Churcher, M. J., Jin, L., Packman, L. C., Shlien, A., Campbell, P., Kirwan, M., Dokal, I., Warren, A. J. Aberrant 3-prime oligodenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. Blood 121: 1028-1038, 2013. [PubMed: 23190533] [Full Text: https://doi.org/10.1182/blood-2012-10-461491]
Mostefai, R., Morice-Picard, F., Boralevi, F., Sautarel, M., Lacombe, D., Stasia, M. J., McGrath, J., Taieb, A. Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco. Am. J. Med. Genet. 146A: 2762-2769, 2008. [PubMed: 18925663] [Full Text: https://doi.org/10.1002/ajmg.a.32524]
Mroczek, S., Krwawicz, J., Kutner, J., Lazniewski, M., Kucinski, I., Ginalski, K., Dziembowski, A. C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3-prime end modification. Genes Dev. 26: 1911-1925, 2012. [PubMed: 22899009] [Full Text: https://doi.org/10.1101/gad.193169.112]
Pianigiani, E., De Aloe, G., Andreassi, A., Rubegni, P., Fimiani, M. Rothmund-Thomson syndrome (Thomson type) and myelodysplasia. Pediat. Derm. 18: 422-425, 2001. [PubMed: 11737690] [Full Text: https://doi.org/10.1046/j.1525-1470.2001.01971.x]
Piccolo, V., Russo, T., Di Pinto, D., Pota, E., Di Martino, M., Piluso, G., Ronchi, A., Argenziano, G., Di Brizzi, E. V., Santoro, C. Poikiloderma with neutropenia and mastocytosis: a case report and a review of dermatological signs. Front. Med. (Lausanne) 8: 680363, 2021. [PubMed: 34179048] [Full Text: https://doi.org/10.3389/fmed.2021.680363]
Suter, A.-A., Itin, P., Heinimann, K., Ahmed, M., Ashraf, T., Fryssira, H., Kini, U., Lapunzina, P., Miny, P., Sommerlund, M., Suri, M., Vaeth, S., Vasudevan, P., Gallati, S. Rothmund-Thomson syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene. Molec. Genet. Genomic Med. 4: 359-366, 2016. [PubMed: 27247962] [Full Text: https://doi.org/10.1002/mgg3.209]
Tanaka, A., Morice-Picard, F., Lacombe, D., Nagy, N., Hide, M., Taieb, A., McGrath, J. Identification of a homozygous deletion mutation in C16orf57 in a family with Clericuzio-type poikiloderma with neutropenia. Am. J. Med. Genet. 152A: 1347-1348, 2010. [PubMed: 20503306] [Full Text: https://doi.org/10.1002/ajmg.a.33455]
Volpi, L., Roversi, G., Colombo, E. A., Leijsten, N., Concolino, D., Calabria, A., Mencarelli, M. A., Fimiani, M., Macciardi, F., Pfundt, R., Schoenmakers, E. F. P. M., Larizza, L. Targeted next-generation sequencing appoints C16orf57 as Clericuzio-type poikiloderma with neutropenia gene. Am. J. Hum. Genet. 86: 72-76, 2010. Note: Erratum: Am. J. Hum. Genet. 87: 445 only, 2010. [PubMed: 20004881] [Full Text: https://doi.org/10.1016/j.ajhg.2009.11.014]
Walne, A. J., Vulliamy, T., Beswick, R., Kirwan, M., Dokal, I. Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome. Hum. Molec. Genet. 19: 4453-4461, 2010. [PubMed: 20817924] [Full Text: https://doi.org/10.1093/hmg/ddq371]