Alternative titles; symbols
HGNC Approved Gene Symbol: TRAPPC2
SNOMEDCT: 51952004;
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38) : X:13,712,245-13,734,620 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.2 | Spondyloepiphyseal dysplasia tarda | 313400 | X-linked recessive | 3 |
TRAPPC2 is a component of the TRAPP multisubunit tethering complex involved in intracellular vesicle trafficking (Scrivens et al., 2011).
The spondyloepiphyseal dysplasia tarda (SEDT; 313400) locus had been mapped by linkage to Xp22 in the approximately 2-Mb interval between DXS16 and DXS987. Gedeon et al. (1999) confirmed and refined this localization to an interval of less than 170 kb by critical recombination events at DXS16 and AFMa124wc1 in 2 families. By genomic sequence analysis, they identified a novel gene, which they designated SEDL, within this region. The SEDL gene encodes a 140-amino acid protein, sedlin, with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport. Northern blot hybridization and RT-PCR analysis indicated that SEDL is widely expressed in tissues, including fibroblasts, lymphoblasts, and fetal cartilage. Two transcripts were detected by Northern blot analysis, one at approximately 2.8 kb encoding the X-linked SEDL and the other at approximately 0.75 kb encoding the truncated transcript of the chromosome 19 pseudogene. The latter is a processed pseudogene with an additional exon 5-prime to the rest of the pseudogene and separated by its sole intron. Gedeon et al. (1999) identified SEDL homologs in yeast, Drosophila, Caenorhabditis elegans, mouse, and rat. The yeast homolog was characterized as a member of a large multiprotein complex called TRAPP (transport protein particle), which has a role in the targeting and fusion of the ER-to-Golgi transport vesicles with their acceptor compartment.
By Northern blot analysis, Mumm et al. (2001) detected additional minor SEDL transcripts of 5.0 and 1.6 kb, the smallest of which may reflect a pseudogene.
Gecz et al. (2000) performed transient transfection studies with tagged recombinant mammalian SEDL proteins in COS-7 cells. The tagged SEDL proteins localized to the perinuclear structures that partly overlapped with the intermediate ER-Golgi compartment. Two human SEDL mutations introduced into SEDL FLAG and GFP constructs led to the misplacement of the SEDL protein primarily to the cell nucleus and partially to the cytoplasm.
Gecz et al. (2000) identified the genomic structure of the SEDL gene. The SEDL gene contains 6 exons and spans a genomic region of approximately 20 kb in Xp22. It has 4 Alu sequences in its 3-prime untranslated region (UTR) and an alternatively spliced MER20 sequence in its 5-prime UTR. Complex alternative splicing was detected for exon 4. Mumm et al. (2001) confirmed the structure of the SEDL gene and identified a potential splice variant lacking exon 2.
Gedeon et al. (1999) determined that the SEDL gene maps to chromosome Xp22. Gecz et al. (2000) identified 7 SEDL pseudogenes in the human genome.
Scrivens et al. (2011) used tandem affinity purification-tagged TRAPPC2 and TRAPPC2L (610970) to identify purified TRAPP complexes from HEK293 cells. Knockdown of individual components of the TRAPP complexes caused Golgi fragmentation and arrested anterograde trafficking, suggesting that the TRAPP complex functions in an early trafficking step between the endoplasmic reticulum and Golgi. Gel filtration analysis suggested that TRAPP complexes can join to form larger oligomers.
Venditti et al. (2012) found that TANGO1 (613455) recruits sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda, and that sedlin is required for the ER export of procollagen, prefibrils of which are too large to fit into typical COPII vesicles. Sedlin bound and promoted efficient cycling of SAR1 (603379), a guanosine triphosphate that can constrict membranes, and thus allowed nascent carriers to grow and incorporate procollagen prefibrils. This joint action of TANGO1 and sedlin sustained the ER export of procollagen, and its derangement may explain the defective chondrogenesis underlying SEDT.
Gedeon et al. (1999) identified 3 dinucleotide deletions in the SEDL gene in affected members of 3 Australian families with SEDT. All 3 mutations caused frameshifts that resulted in protein truncation, arousing speculation that less severe missense mutations of SEDL may have different phenotypic effects, such as precocious osteoarthritis only.
Gedeon et al. (2001) reviewed the spectrum of mutations found in 30 of 36 unrelated cases of X-linked SEDT ascertained from different ethnic populations. It brought the total number of different disease-associated mutations to 21 and showed that they were distributed throughout the SEDL gene. Four recurrent mutations accounted for 13 of the 30 (43%). Haplotype analyses and the diverse ethnic origins of the patients supported recurrent mutations. Two patients with large deletions of SEDL exons were found, 1 with childhood onset of painful complications, the other relatively free of additional symptoms. Since no clear genotype/phenotype correlation could be established, they concluded that the complete unaltered SEDL gene product is essential for normal bone growth.
Tiller et al. (2001) determined that the SEDL gene escapes X inactivation. They reported that the closest flanking genes identified at Xp22.2 also escape X inactivation. Clustering supported a model in which reasonable mechanisms may control the expression of genes that escape X inactivation. Most mutations in SEDL patients are predicted to truncate severely the protein product or eliminate it entirely. The observation that SEDL escapes X inactivation suggests that haploinsufficiency at the locus is inadequate to produce any phenotypic changes in female SEDL carriers. Although Whyte et al. (1999) observed subtle radiographic changes in older SEDL carriers, no signs or symptoms of premature osteoarthritis were noted in the women of the family reported by Tiller et al. (2001) or those reported by Gedeon et al. (1999).
Christie et al. (2001) characterized the SEDL mutations in 4 unrelated spondyloepiphyseal dysplasia tarda kindreds of European origin. They identified 2 nonsense and 2 intragenic deletional frameshift mutations. The nonsense mutations occurred in exons 4 and 6. Both of the intragenic deletions, which were approximately 750 and 1300 to 1445 bp in size, involved intron 5 and part of exon 6 and resulted in frameshifts that led to premature termination signals.
Grunebaum et al. (2001) identified a missense mutation (300202.0007) in a 4-generation family with late-onset SED. Grunebaum et al. (2001) suggested that the mild phenotype in this family might be caused by a missense rather than a nonsense mutation.
The possibility that some mutations in the SEDL gene may result in a mild phenotype like that of early primary osteoarthritis prompted Fiedler et al. (2002) to collect a cohort of 37 male patients (age 50.6 +/- 7.6 years) with either early end-stage primary osteoarthritis of the hip (26 patients) or knee (11 patients). Cases with risk factors for secondary osteoarthritis, such as congenital hip dysplasia, rheumatoid arthritis, joint trauma, obesity, or diabetes mellitus, were excluded. Seven patients were stated to be the shortest in the family, while from 8 patients the father (with 158 cm), and from 4 the brother was the shortest member. Six fathers of the patients and 1 brother needed joint replacement because of end-stage osteoarthritis. Fiedler et al. (2002) detected no mutations in the coding sequence of SEDL and found no polymorphism indicating a highly conserved gene. Their findings supported previous results of high homology between different species (Gedeon et al., 2001; Gecz et al., 2000). The results indicated that mutations in the coding sequence of SEDL are not a common cause of early primary osteoarthritis in men.
Jang et al. (2002) reported the 2.4-angstrom resolution structure of mouse SEDL, which revealed an unexpected similarity to the structures of the N-terminal regulatory domain of 2 SNAREs, Ykt6p (606209) and SEC22B (604029), despite no sequence homology to these proteins. The similarity and the presence of an unusually large number of solvent-exposed apolar residues of SEDL suggested that it serves regulatory and/or adaptor functions through multiple protein-protein interactions. Jang et al. (2002) noted that of the 4 known missense mutations responsible for SEDT, 3 map to the protein interior, where the mutations would disrupt the structure, and the fourth maps on a surface at which the mutation might abrogate functional interactions with a partner protein.
In a family with X-linked spondyloepiphyseal dysplasia tarda (SEDT; 313400), Gedeon et al. (1999) observed a dinucleotide deletion of TT at positions 53 and 54 in exon 3 of the SEDL gene, in a string of 5 thymines.
In a family with X-linked spondyloepiphyseal dysplasia tarda (SEDT; 313400), Gedeon et al. (1999) reported a dinucleotide deletion of TG at positions 191 to 192 in exon 4 of the SEDL gene. Gedeon et al. (2001) found that this was a recurrent mutation. The results of haplotype analyses and the diverse ethnic origins of patients supported recurrence of the mutation.
In a family with X-linked spondyloepiphyseal dysplasia tarda (SEDT; 313400), Gedeon et al. (1999) identified a deletion of AT at positions 157 and 158 in exon 3 of the SEDL gene.
Whyte et al. (1999) described the clinical and radiographic evaluation of a 6-generation kindred from Arkansas with X-linked recessive spondyloepiphyseal dysplasia tarda (SEDT; 313400). Mumm et al. (2000) investigated this family by mutation analysis. In an affected man and obligate carrier woman, they found a 5-bp deletion (AAGAC) in exon 5 of the sedlin gene. The defect causes a frameshift, resulting in 8 missense amino acids and premature termination. The 5-bp deletion was then demonstrated to segregate with SEDT in the 4 living generations, including 8 affected males and 9 obligate carrier females. Furthermore, the deletion was identified in 4 females who potentially were heterozygous carriers for SEDT.
Gedeon et al. (2001) stated that the deletion of nucleotides 271-275 was recurrent. The results of haplotype analyses and the diverse ethnic origins of patients with spondyloepiphyseal dysplasia tarda (SEDT; 313400) supported recurrent mutations.
Tiller et al. (2001) characterized an exon-skipping mutation in 2 unrelated families with spondyloepiphyseal dysplasia tarda (SEDT; 313400): IVS3+5G-A at the intron 3 splice donor site. Using RT-PCR, they demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame. RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation. Homologs of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila, C. elegans, and S. cerevisiae. The yeast homolog, p20, has a putative role in vesicular transport from ER to Golgi complex. The data suggested that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis.
Grunebaum et al. (2001) identified a 4-generation family with late-onset spondyloepiphyseal dysplasia (SEDT; 313400) caused by a T-to-C substitution at nucleotide 248 in exon 5 of the SEDL gene, resulting in the substitution of a phenylalanine by serine residue at amino acid 83 (p83). The phenotype in this family was mild, and Grunebaum et al. (2001) speculated that this might be due to the presence of a missense rather than a nonsense mutation in this family.
In a 14-year-old Japanese boy with late-onset spondyloepiphyseal dysplasia (SEDT; 313400), Takahashi et al. (2002) identified homozygosity for a 391C-T transition in the SEDL gene, resulting in a gln131 (CAG)-to-ter (TAG) (Q131X) substitution. The mother was heterozygous for the mutation. There were 5 affected males in 3 generations connected through carrier females.
In a 16-year-old Taiwanese boy with late-onset spondyloepiphyseal dysplasia (SEDT; 313400), the single affected individual in his family, Shi et al. (2002) identified a 329C-A transversion in exon 6 of the SEDL gene, resulting in a TCA (ser) to TAA (ter) change at codon 329 (S329X). The authors stated that 'according to the family history,' 4 male children and an uncle on the maternal side had the clinical features of SEDT. Clinical details were not provided.
In an Italian family with 2 brothers affected with spondyloepiphyseal dysplasia tarda (SEDT; 313400) of different degrees of severity and with pubertal delay as an associated finding, Shaw et al. (2003) found a mutation in the rare, noncanonical 5-prime splice site of intron 4 of the SEDL gene: IVS4+4T-C. RT-PCR analysis showed that this mutation caused alternative splicing of exon 5 and, as a consequence, inclusion of exon 4b sequence. This gave rise to an altered, truncated SEDL protein.
In an Ashkenazi Jewish family with spondyloepiphyseal dysplasia tarda (SEDT; 313400), Bar-Yosef et al. (2004) identified a deletion of nucleotide A at position 613 (613delA) in exon 6 of the SEDL gene, resulting in truncation at codon 139 of the 140-codon-long protein. The authors noted that the mutation also predicts a val130-to-phe substitution that would likely interfere with proper folding of the protein. Bar-Yosef et al. (2004) stated that this was the first report of an SEDL mutation in a Jewish family.
In a Turkish male with features suggestive of spondyloepiphyseal dysplasia tarda (SEDT; 313400) and his unaffected mother, Davis et al. (2014) identified a 3-bp deletion in intron 4 of the TRAPPC2 gene, c.341-(11_9)delAAT, by exome sequencing. RT-PCR analysis of cell lysates from the patient showed 2 aberrantly spliced signals. Sanger sequencing revealed that the c.341-(11_9)delAAT leads to exon 5 skipping. The authors concluded that the mutation disrupts the function of sedlin.
Bar-Yosef, U., Ohana, E., Hershkovitz, E., Perlmuter, S., Ofir, R., Birk, O. S. X-linked spondyloepiphyseal dysplasia tarda: a novel SEDL mutation in a Jewish Ashkenazi family and clinical intervention considerations. Am. J. Med. Genet. 125A: 45-48, 2004. [PubMed: 14755465] [Full Text: https://doi.org/10.1002/ajmg.a.20435]
Christie, P. T., Curley, A., Nesbit, M. A., Chapman, C., Genet, S., Harper, P. S., Keeling, S. L., Wilkie, A. O. M., Winter, R. M., Thakker, R. V. Mutational analysis in X-linked spondyloepiphyseal dysplasia tarda. J. Clin. Endocr. Metab. 86: 3233-3236, 2001. [PubMed: 11443194] [Full Text: https://doi.org/10.1210/jcem.86.7.7688]
Davis, E. E., Savage, J. H., Willer, J. R., Jiang, Y.-H., Angrist, M., Androutsopoulos, A., Katsanis, N. Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT. Clin. Genet. 85: 359-364, 2014. [PubMed: 23656395] [Full Text: https://doi.org/10.1111/cge.12189]
Fiedler, J., Bittner, M., Puhl, W., Brenner, R. E. Mutations in the X-linked spondyloepiphyseal dysplasia tarda (SEDL) coding sequence are not a common cause of early primary osteoarthritis in men. (Letter) Clin. Genet. 62: 94-95, 2002. [PubMed: 12123495] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.620114.x]
Gecz, J., Hillman, M. A., Gedeon, A. K., Cox, T. C., Baker, E., Mulley, J. C. Gene structure and expression study of the SEDL gene for spondyloepiphyseal dysplasia tarda. Genomics 69: 242-251, 2000. [PubMed: 11031107] [Full Text: https://doi.org/10.1006/geno.2000.6326]
Gedeon, A. K., Colley, A., Jamieson, R., Thompson, E. M., Rogers, J., Sillence, D., Tiller, G. E., Mulley, J. C., Gecz, J. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nature Genet. 22: 400-404, 1999. [PubMed: 10431248] [Full Text: https://doi.org/10.1038/11976]
Gedeon, A. K., Tiller, G. E., Le Merrer, M., Heuertz, S., Tranebjaerg, L., Chitayat, D., Robertson, S., Glass, I. A., Savarirayan, R., Cole, W. G., Rimoin, D. L., Kousseff, B. G., Ohashi, H., Zabel, B., Munnich, A., Gecz, J., Mulley, J. C. The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. Am. J. Hum. Genet. 68: 1386-1397, 2001. [PubMed: 11349230] [Full Text: https://doi.org/10.1086/320592]
Grunebaum, E., Arpaia, E., MacKenzie, J. J., Fitzpatrick, J., Ray, P. N., Roifman, C. M. A missense mutation in the SEDL gene results in delayed onset of X linked spondyloepiphyseal dysplasia in a large pedigree. (Letter) J. Med. Genet. 38: 409-411, 2001. [PubMed: 11424925] [Full Text: https://doi.org/10.1136/jmg.38.6.409]
Jang, S. B., Kim, Y.-G., Cho, Y.-S., Suh, P.-G., Kim, K.-H., Oh, B.-H. Crystal structure of SEDL and its implications for a genetic disease spondyloepiphyseal dysplasia tarda. J. Biol. Chem. 277: 49863-49869, 2002. [PubMed: 12361953] [Full Text: https://doi.org/10.1074/jbc.M207436200]
Mumm, S., Christie, P. T., Finnegan, P., Jones, J., Dixon, P. H., Pannett, A. A. J., Harding, B., Gottesman, G. S., Thakker, R. V., Whyte, M. P. A five-base pair deletion in the sedlin gene causes spondyloepiphyseal dysplasia tarda in a six-generation Arkansas kindred. J. Clin. Endocr. Metab. 85: 3343-3347, 2000. [PubMed: 10999831] [Full Text: https://doi.org/10.1210/jcem.85.9.6840]
Mumm, S., Zhang, X., Vacca, M., D'Esposito, M., Whyte, M. P. The sedlin gene for spondyloepiphyseal dysplasia tarda escapes X-inactivation and contains a non-canonical splice site. Gene 273: 285-293, 2001. [PubMed: 11595175] [Full Text: https://doi.org/10.1016/s0378-1119(01)00571-6]
Scrivens, P. J., Noueihed, B., Shahrzad, N., Hul, S., Brunet, S., Sacher, M. C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking. Molec. Biol. Cell 22: 2083-2093, 2011. [PubMed: 21525244] [Full Text: https://doi.org/10.1091/mbc.E10-11-0873]
Shaw, M. A., Brunetti-Pierri, N., Kadasi, L., Kovacova, V., Van Maldergem, L., De Brasi, D., Salerno, M., Gecz, J. Identification of three novel SEDL mutations, including mutation in the rare, non-canonical splice site of exon 4. Clin. Genet. 64: 235-242, 2003. [PubMed: 12919139] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00132.x]
Shi, Y.-R., Lee, C.-C., Hsu, Y.-A., Wang, C.-H., Tsai, F.-J. A novel nonsense mutation of the sedlin gene in a family with spondyloepiphyseal dysplasia tarda. Hum. Hered. 54: 54-56, 2002. [PubMed: 12446987] [Full Text: https://doi.org/10.1159/000066694]
Takahashi, T., Takahashi, I., Tsuchida, S., Oyama, K., Komatsu, M., Saito, H., Takada, G. An SEDL gene mutation in a Japanese kindred of X-linked spondyloepiphyseal dysplasia tarda. (Letter) Clin. Genet. 61: 319-320, 2002. Note: Erratum: Clin. Genet. 64: 375 only, 2003. [PubMed: 12030902] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.610416.x]
Tiller, G. E., Hannig, V. L., Dozier, D., Carrel, L., Trevarthen, K. C., Wilcox, W. R., Mundlos, S., Haines, J. L., Gedeon, A. K., Gecz, J. A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda. Am. J. Hum. Genet. 68: 1398-1407, 2001. [PubMed: 11326333] [Full Text: https://doi.org/10.1086/320594]
Venditti, R., Scanu, T., Santoro, M., Di Tullio, G., Spaar, A., Gaibisso, R., Beznoussenko, G. V., Mironov, A. A., Mironov, A., Jr., Zelante, L., Piemontese, M. R., Notarangelo, A., Malhotra, V., Vertel, B. M., Wilson, C., De Matteis, M. A. Sedlin controls the ER export of procollagen by regulating the Sar1 cycle. Science 337: 1668-1672, 2012. [PubMed: 23019651] [Full Text: https://doi.org/10.1126/science.1224947]
Whyte, M. P., Gottesman, G. S., Eddy, M. C., McAlister, W. H. X-linked recessive spondyloepiphyseal dysplasia tarda: clinical and radiographic evolution in a 6-generation kindred and review of the literature. Medicine 78: 9-25, 1999. [PubMed: 9990351] [Full Text: https://doi.org/10.1097/00005792-199901000-00002]