Alternative titles; symbols
HGNC Approved Gene Symbol: SKIC2
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,959,175-31,969,751 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Trichohepatoenteric syndrome 2 | 614602 | Autosomal recessive | 3 |
Lee et al. (1995) identified a human cDNA with sequence homology to the yeast nucleolar protein gene SKI2. SKI2 belongs to a group of 6 yeast genes that repress the copy number of single- and double-stranded RNA viruses. Lee et al. (1995) identified the cDNA by immunoscreening an expression library with a monoclonal antibody raised against bovine pigmented retinal cells. The antibody recognizes a 90-kD nuclear antigen in a number of species.
Helicases are involved in DNA replication, DNA repair, recombination, transcription, RNA splicing, and translation. Dangel et al. (1995) cloned a putative human helicase, which they designated SKI2W, that is located between the RD gene (154040) and a gene they called RP1 (D6S60E; see Shen et al., 1994) in the class III region of the major histocompatibility complex on chromosome 6. The gene occurs within an approximately 11-kb span between RD and RP1. The cDNA was isolated from a set of lymphocyte libraries and the predicted 1,246-amino acid protein (137 kD) contains motifs associated with RNA helicases and has a leucine zipper domain. The protein shares extensive similarity (39% identity) to the yeast Ski2p gene which is involved in the inhibition of translation of non-polyadenylated RNA and has an important role in defense against infection by single- and double-stranded RNA viruses. The authors showed that the recombinant SKI2W protein exhibits ATPase activity. Northern blots indicated a 3.9-kb transcript in a variety of human transformed lines. Dangel et al. (1995) stated that this gene was very similar in sequence to that reported by Lee et al. (1995) and that discrepancies between the 2 sequences were probably the result of cloning artifacts.
Inherently unstable mammalian mRNAs contain AU-rich elements (AREs) within their 3-prime untranslated regions. In yeast, 3-prime-to-5-prime mRNA degradation is mediated by the exosome, a multisubunit particle. Chen et al. (2001) purified and characterized the human exosome by mass spectrometry and found its composition to be similar to its yeast counterpart. They identified the following protein subunits within the human exosome: p7, which is homologous to the yeast Rrp4 protein (602238); p8, which is homologous to the yeast Rrp42 protein (606488); p9, which is homologous to the yeast Rrp43 protein (OIP2; 606019); p10, which is homologous to the yeast Rrp40 protein (606489); p11, which is homologous to the yeast Mtr3 protein (606490); p12A, which is homologous to the yeast Rrp41 protein (606491); p12B, which is homologous to the yeast Rrp46 protein (606492); and p13, which is homologous to the yeast Csl4 protein (606493). They also identified 2 exosome-associated factors, p1 (SKIV2L) and p14 (MPP6; 605500), that were not homologous to any yeast exosome components.
By genomic sequence analysis, Yang et al. (1998) determined that SKIV2L is a polymorphic gene that spans 11 kb and contains 28 exons.
Lee et al. (1995) isolated genomic clones and mapped the human homolog of SKI2 gene to 6p21 by fluorescence in situ hybridization. By genomic sequence analysis, Yang et al. (1998) determined that the SKIV2L gene is located 171 bp downstream from the RD gene.
Stumpf (2022) mapped the SKIC2 gene to chromosome 6p21.33 based on an alignment of the SKIC2 sequence (GenBank BC015758) with the genomic sequence (GRCh38).
Using a cell-free RNA decay system, Chen et al. (2001) demonstrated that the mammalian exosome is required for rapid degradation of ARE-containing RNAs but not for poly(A) shortening. They found that the mammalian exosome does not recognize ARE-containing RNAs on its own. ARE recognition required certain ARE-binding proteins that could interact with the exosome and recruit it to unstable RNAs, thereby promoting their rapid degradation.
In 6 unrelated patients with typical trichohepatoenteric syndrome (THES2; 614602) who were known to be negative for mutation in the TTC37 gene (614589), Fabre et al. (2012) sequenced the candidate gene SKIV2L and identified homozygosity or compound heterozygosity for 8 different mutations, respectively, in all patients (see, e.g., 600478.0001-600478.0003). All of the unaffected parents available for analysis were heterozygous for 1 of the mutations identified in their child.
In 5 sibs from 3 consanguineous Saudi families with THES who also exhibited cafe-au-lait spots below the waist, Monies et al. (2015) identified homozygosity for a 21-bp deletion in the SKIV2L gene (600478.0004) that was confirmed by Sanger sequencing and segregated with disease in each family.
In a 17-month-old Han Chinese boy with THES, Zheng et al. (2016) analyzed the SKIV2L gene and identified compound heterozygosity for a nonsense mutation (R374X; 600478.0005) and a missense mutation (G631S; 600478.0006), for which his unaffected parents were heterozygous.
In a French patient with trichohepatoenteric syndrome (THES2; 614602), Fabre et al. (2012) identified compound heterozygosity for a c.848G-A transition (c.848G-A, NM_006929.4) in the SKIV2L (SKIC2) gene, resulting in a trp283-to-ter (W283X) substitution, and a c.1022T-G transversion, resulting in a val341-to-gly (V341G; 600478.0002) substitution.
For discussion of the c.1022T-G transversion (c.1022T-G, NM_006929.4) in the SKIV2L (SKIC2) gene, resulting in a val341-to-gly (V341G) substitution, that was found in compound heterozygous state in a patient with trichohepatoenteric syndrome (THES2; 614602) by Fabre et al. (2012), see 600478.0001.
In a North African patient with trichohepatoenteric syndrome-2 (THES2; 614602), Fabre et al. (2012) identified homozygosity for a 1-bp insertion (c.1635insA, NM_006929.4) in the SKIV2L (SKIC2) gene, causing a frameshift predicted to result in a premature termination codon (Gly546ArgfsTer35).
In 5 sibs from 3 consanguineous Saudi families (families 1, 3, and 4) with THES who also exhibited cafe-au-lait spots below the waist (THES2; 614602), Monies et al. (2015) identified homozygosity for a 21-bp deletion (c.3559_3579del) in exon 28 of the SKIC2 gene, resulting in the in-frame deletion of 7 amino acids (p.1187_1193del) within the DOB1/SK12/helY-like DEAD box helicase C-terminal domain. Sanger sequencing confirmed the deletion and its segregation with disease in each family. Functional studies of the mutation were not performed.
In a 17-month-old Han Chinese boy with trichohepatoenteric syndrome (THES2; 614602), Zheng et al. (2016) identified compound heterozygosity for a c.1120C-T transition (c.1120C-T, NM_600478) in the SKIC2 gene, resulting in an arg374-to-ter (R374X) substitution, and a c.1891G-A transition, resulting in a gly631-to-ser (G631X) substitution at a highly conserved residue. Functional studies of the mutations were not performed.
For discussion of the c.1891G-A transition (c.1891G-A, NM_600478) in the SKIC2 gene, resulting in a gly631-to-ser (G631S) substitution, that was found in compound heterozygous state in a 17-month-old Han Chinese boy with trichohepatoenteric syndrome (THES2; 614602) by Zheng et al. (2016), see 600478.0005.
Chen, C.-Y., Gherzi, R., Ong, S.-E., Chan, E. L., Raijmakers, R., Pruijn, G. J. M., Stoecklin, G., Moroni, C., Mann, M., Karin, M. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107: 451-464, 2001. [PubMed: 11719186] [Full Text: https://doi.org/10.1016/s0092-8674(01)00578-5]
Dangel, A. W., Shen, L., Mendoza, A. R., Wu, L.-c., Yu, C. Y. Human helicase gene SKI2W in the HLA class III region exhibits striking structural similarities to the yeast antiviral gene SKI2 and to the human gene KIAA0052: emergence of a new gene family. Nucleic Acids Res. 23: 2120-2126, 1995. [PubMed: 7610041] [Full Text: https://doi.org/10.1093/nar/23.12.2120]
Fabre, A., Charroux, B., Martinez-Vinson, C., Roquelaure, B., Odul, E., Sayar, E., Smith, H., Colomb, V., Andre, N., Hugot, J.-P., Goulet, O., Lacoste, C., Sarles, J., Royet, J., Levy, N., Badens, C. SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. Am. J. Hum. Genet. 90: 689-692, 2012. [PubMed: 22444670] [Full Text: https://doi.org/10.1016/j.ajhg.2012.02.009]
Lee, S.-G., Lee, I., Park, S. H., Kang, C., Song, K. Identification and characterization of a human cDNA homologous to yeast SKI2. Genomics 25: 660-666, 1995. [PubMed: 7759100] [Full Text: https://doi.org/10.1016/0888-7543(95)80008-a]
Monies, D. M., Rahbeeni, Z., Abouelhoda, M., Naim, E. A., Al-Younes, B., Meyer, B. F., Al-Mehaidib, A. Expanding phenotypic and allelic heterogeneity of tricho-hepato-enteric syndrome. J. Pediat. Gastroent. Nutr. 60: 352-356, 2015. [PubMed: 25714577] [Full Text: https://doi.org/10.1097/MPG.0000000000000627]
Shen, L., Wu, L. C., Sanlioglu, S., Chen, R., Mendoza, A. R., Dangel, A. W., Carroll, M. C., Zipf, W. B., Yu, C. Y. Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and the C4B genes in the HLA class III region: molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplication. J. Biol. Chem. 269: 8466-8476, 1994. [PubMed: 8132574]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/29/2022.
Yang, Z., Shen, L., Dangel, A. W., Wu, L.-C., Yu, C. Y. Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA. Genomics 53: 338-347, 1998. [PubMed: 9799600] [Full Text: https://doi.org/10.1006/geno.1998.5499]
Zheng, B., Pan, J., Jin, Y., Wang, C., Liu, Z. Targeted next-generation sequencing identification of a novel missense mutation of the SKIV2L gene in a patient with trichohepatoenteric syndrome. Molec. Med. Rep. 14: 2107-2110, 2016. [PubMed: 27431780] [Full Text: https://doi.org/10.3892/mmr.2016.5503]