Alternative titles; symbols
HGNC Approved Gene Symbol: TRAPPC10
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:44,012,309-44,106,552 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Neurodevelopmental disorder with microcephaly, short stature, and speech delay | 620027 | Autosomal recessive | 3 |
The TRAPPC10 gene encodes a component of the conserved transport protein particle II complex (TRAPP II) that, along with TRAPPC9 (611966), plays a fundamental role in secretory and endocytic subcellular trafficking pathways, particularly in the Golgi apparatus (summary by Rawlins et al., 2022).
In an attempt to isolate the gene involved in the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1; 254800) or in autoimmune polyglandular disease type 1 (APECED; 240300), Yamakawa et al. (1995) constructed bacterial artificial chromosome (BAC) contigs of the candidate region, 21q22.3, as well as a 14-week trisomy 21 fetal brain cDNA library. A direct cDNA selection technique was applied to gene identification using the BAC contigs. They isolated and characterized a novel gene, which they designated EHOC-1 for epilepsy, holoprosencephaly candidate-1, that was defined by 3 overlapping but distinct cDNAs. This gene mapped less than 45 kb centromeric of D21S25 and spanned at least 56 kb of genomic DNA. Northern blot analysis revealed that 8-, 7.5-, and 5.3-kb transcripts are ubiquitously expressed in adult tissues. DNA sequence analysis showed a complete coding sequence of 3,570 bp with multiple putative transmembrane domains that shared partial homology with transmembrane proteins including sodium channel proteins.
Nagamine et al. (1997) cloned and sequenced a cDNA and genomic clone of this gene, which they termed transmembrane protein-1 (TMEM1). They found several errors in the sequence reported by Yamakawa et al. (1995), including one that changes the length of the encoded sequence from 1,190 amino acids to 1,259 amino acids.
Lafreniere et al. (1997) presented the isolation, cDNA sequence, genomic organization, and polymorphism analysis of an expressed sequence derived from the distal tip of human chromosome 21. This sequence, which they referred to as GT334, had been independently identified and corresponds to EHOC1 (TMEM1). An open reading frame potentially encodes a 1,259-amino acid protein. They identified polymorphisms useful for genetic mapping of disorders localized to this region.
Nagamine et al. (1997) reported that the TMEM1 gene consists of 23 exons spanning 94 kb of genomic DNA. Using a 450-kb cosmid/BAC contig, they found that the gene is located between markers D21S1460 and D21S154, just proximal to the 5-prime end of the neighboring gene PWP2H (601475).
Lafreniere et al. (1997) found that the TMEM1 gene contains 23 exons and spans an estimated 95 kb of genomic DNA. A pseudogene of a histone gene was identified in the third intron.
Using BAC contigs, Yamakawa et al. (1995) identified the TMEM1 gene on chromosome 21q22.3.
In 2 brothers, born of consanguineous Pakistani parents (family MR107), with neurodevelopmental disorder with microcephaly, short stature, and speech delay (NEDMISS; 620027), Santos-Cortez et al. (2018) identified a homozygous missense mutation in the TRAPPC10 gene (P929L; 602103.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was not present in the gnomAD database. Functional studies of the variant were not performed.
In 8 affected members of a consanguineous Pakistani family (family 1) with NEDMISS, Rawlins et al. (2022) identified a homozygous frameshift mutation in the TRAPPC10 gene (602103.0002). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies in yeast showed that the frameshift mutation and the P929L mutation identified by Santos-Cortez et al. (2018) reduced the interaction of TRAPPC10 with TRAPPC2L (610970) compared to controls. Neither mutation was able to fully rescue Golgi membrane trafficking defects in TRAPPC10-null HEK293 cells, whereas expression of wildtype TRAPPC10 could rescue the phenotype. The findings were consistent with the mutations causing partial functional defects.
Rawlins et al. (2022) found that Trappc10-null mice had smaller total brain area compared to wildtype, with specific reductions in the size of the corpus callosum, regions of the hippocampus, anterior commissure, and internal capsule. Only white matter structures were affected. There was loss of myelination in these regions, but oligodendrocyte numbers were normal. These findings recapitulated the microcephalic phenotype observed in human patients with mutations in the TRAPPC10 gene.
In 2 brothers, born of consanguineous Pakistani parents (family MR107), with neurodevelopmental disorder with microcephaly, short stature, and speech delay (NEDMISS; 620027), Santos-Cortez et al. (2018) identified a homozygous c.2786C-T transition (c.2786C-T, NM_003274.4) in the TRAPPC10 gene, resulting in a pro929-to-leu (P929L) substitution. The mutation, which as found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was not present in the gnomAD database. Functional studies of the variant were not performed.
Rawlins et al. (2022) restudied the family reported by Santos-Cortez et al. (2018), noting that the mutation occurred in exon 18 at a highly conserved residue. In vitro functional expression studies in yeast showed that the mutant protein had reduced interaction with TRAPPC2L (610970) compared to controls. The mutation was unable to fully rescue Golgi membrane trafficking defects in TRAPPC10-null HEK293 cells, whereas expression of wildtype TRAPPC10 could rescue the phenotype. The findings were consistent with the mutation causing partial functional defects. There was also evidence that the mutant protein was subject to enhanced degradation within the cell. The patients also showed behavioral abnormalities.
In 8 affected members of a consanguineous Pakistani family (family 1) with neurodevelopmental disorder with microcephaly, short stature, and speech delay (NEDMISS; 620027), Rawlins et al. (2022) identified a homozygous 1-bp deletion (c.3392delG, NM_003274.4) in the penultimate exon of the TRAPPC10 gene, resulting in frameshift and premature termination of the protein (Gly1131ValfsTer19). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies in yeast showed that the mutant protein had reduced interaction with TRAPPC2L (610970) compared to controls. Studies on a patient-derived lymphoblastoid cell line showed absence of the TRAPPC10 protein, as well as absence of full-length TRAPPC9 (611966), an interacting protein. The mutant protein was unable to fully rescue Golgi membrane trafficking defects in TRAPPC10-null HEK293 cells, whereas expression of wildtype TRAPPC10 could rescue the phenotype. The findings were consistent with the mutation causing partial functional defects. There was also evidence that the mutant protein was subject to enhanced degradation within the cell. Other features included hypotonia and behavioral abnormalities; 4 patients had seizures.
Lafreniere, R. G., Kibar, Z., Rochefort, D. L., Han, F.-Y., Fon, E. A., Dube, M.-P., Kang, X., Baird, S., Korneluk, R. G., Rommens, J. M., Rouleau, G. A. Genomic structure of the human GT334 (EHOC-1) gene mapping to 21q22.3. Gene 198: 313-321, 1997. [PubMed: 9370297] [Full Text: https://doi.org/10.1016/s0378-1119(97)00333-8]
Nagamine, K., Kudoh, J., Kawasaki, K., Minoshima, S., Asakawa, S., Ito, F., Shimizu, N. Genomic organization and complete nucleotide sequence of the TMEM1 gene on human chromosome 21q22.3. Biochem. Biophys. Res. Commun. 235: 185-190, 1997. [PubMed: 9196060] [Full Text: https://doi.org/10.1006/bbrc.1997.6758]
Rawlins, L. E., Almousa, H., Khan, S., Collins, S. C., Milev, M. P., Leslie, J., Saint-Dic, D., Khan, V., Hincapie, A. M., Day, J. O., McGavin, L., Rowley, C., and 9 others. Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice. PLoS Genet. 18: e1010114, 2022. [PubMed: 35298461] [Full Text: https://doi.org/10.1371/journal.pgen.1010114]
Santos-Cortez, R. L. P., Khan, V., Khan, F. S., Mughal, Z.-N., Chakchouk, I., Lee, K., Rasheed, M., Hamza, R., Acharya, A., Ullah, E., Saqib, M. A. N., Abbe, I., and 11 others. Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability. Hum. Genet. 137: 735-752, 2018. [PubMed: 30167849] [Full Text: https://doi.org/10.1007/s00439-018-1928-6]
Yamakawa, K., Mitchell, S., Hubert, R., Chen, X.-N., Colbern, S., Huo, Y.-K., Gadomski, C., Kim, U.-J., Korenberg, J. R. Isolation and characterization of a candidate gene for progressive myoclonus epilepsy on 21q22.3. Hum. Molec. Genet. 4: 709-716, 1995. [PubMed: 7633421] [Full Text: https://doi.org/10.1093/hmg/4.4.709]