Alternative titles; symbols
HGNC Approved Gene Symbol: TMTC3
Cytogenetic location: 12q21.32 Genomic coordinates (GRCh38): 12:88,142,307-88,199,887 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.32 | Lissencephaly 8 | 617255 | Autosomal recessive | 3 |
TMTC3 is a positive regulator of the endoplasmic reticulum (ER) stress response (Racape et al., 2011).
Racape et al. (2011) reported that the deduced 914-amino acid TMTC3 transmembrane protein, which they called SMILE, contains 10 tetratricopeptide repeats (TPRs) and is highly conserved. Immunohistochemical analysis of cultured human odontoblasts revealed SMILE localization in vesicles and in the ER.
Yun and Vu (2012) cloned mouse Smile. The deduced 963-amino acid protein has 9 transmembrane domains and 10 TPRs.
By yeast 2-hybrid screening of a human brown adipocyte cDNA library, Racape et al. (2011) found that SMILE interacted with PDIA3 (602046), which is involved in protein folding and ER stress response. Knockdown of SMILE in HeLa cells reduced expression of genes involved in protein metabolism, including several that encode proteasome subunits, and reduced proteasome chymotrypsin-like activity (see PSMD5, 604452). Silencing of SMILE in HeLa cells impaired long-term survival, increased ER stress, and sensitized cells to further ER stress. In primary human keratinocytes, silencing SMILE caused elevated expression of XBP1 (194355), a stress response protein that directs transcription of genes involved in the unfolded protein response. Using RT-PCR, Racape et al. (2011) found that expression of SMILE mRNA was significantly reduced in peripheral blood mononuclear cells (PBMCs) from kidney transplant patients under standard immunosuppressive therapy with either stable graft function or deteriorating graft function and chronic antibody-mediated rejection compared with PBMCs from operationally tolerant kidney transplant patients.
Hartz (2016) mapped the TMTC3 gene to chromosome 12q21.32 based on an alignment of the TMTC3 sequence (GenBank AK074973) with the genomic sequence (GRCh38).
In 9 children from 6 consanguineous families, mostly of Arab origin, with lissencephaly-8 (LIS8; 617255), Jerber et al. (2016) identified biallelic mutations in the TMTC3 gene (see, e.g., 617218.0001-617218.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the mutations resulted in a truncated protein, although 2 affected sibs carried a homozygous missense mutation. Functional studies of the variants and studies of patient cells were not performed, but Jerber et al. (2016) postulated a loss-of-function effect.
Yun and Vu (2012) obtained Smile -/- mice at the expected mendelian ratio, but few survived to 3 weeks of age. Smile -/- lungs displayed defects in both airway branching morphogenesis during fetal lung development and alveolarization after birth. These defects were associated with reduced numbers of bronchial smooth muscle cells in the peribronchial subepithelial region and clefts and myofibroblasts at alveolar septae. Smile -/- lungs showed reduced expression of Fgf10 (602115) and its downstream target Bmp4 (112262), which are important for bronchial smooth muscle formation. In vitro, Smile -/- embryonic fibroblasts showed reduced myofibroblast formation in response to Tgf-beta (TGFB1; 190180). Yun and Vu (2012) concluded that Smile specifies bronchial smooth muscle and lung alveolar myofibroblast lineages.
In girl, born of consanguineous Egyptian parents (family I), with lissencephaly-8 (LIS8; 617255), Jerber et al. (2016) identified compound heterozygous mutations in the TMTC3 gene: a 1-bp deletion (c.1462delA, NM_181783.3) in exon 11, resulting in a frameshift and premature termination (Arg488GlufsTer6), and a c.2617C-T transition in exon 14, resulting in a gln873-to-ter (Q873X; 617218.0002) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the dbSNP (build 138), 1000 Genomes Project, or ExAC databases. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.2617C-T transition (c.2617C-T, NM_181783.3) in the TMTC3 gene, resulting in a gln873-to-ter (Q873X) substitution, that was found in compound heterozygous state in a patient with lissencephaly-8 (LIS8; 617255) by Jerber et al. (2016), see 617218.0001.
In 2 sisters, born of consanguineous parents from Yemen (family II), with lissencephaly-8 (LIS8; 617255), Jerber et al. (2016) identified a homozygous 2-bp insertion (c.1959_1960TT, NM_181783.3) in the TMTC3 gene, resulting in a frameshift and premature termination (Arg654LeufsTer6). 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 dbSNP (build 138), 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs, born of consanguineous Lebanese parents (family IV), with lissencephaly-8 (LIS8; 617255), Jerber et al. (2016) identified a homozygous c.199C-G transversion (c.199C-G, NM_181783.3) in the TMTC3 gene, resulting in a his67-to-asp (H67D) substitution at a highly conserved residue. 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 dbSNP (build 138), 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs, born of consanguineous Turkish parents (family V), with lissencephaly-8 (LIS8; 617255), Jerber et al. (2016) identified a homozygous c.3G-A transition (c.3G-A, NM_181783.3) in the TMTC3 gene, resulting in a met1-to-? (M1?) substitution in the initiation codon. 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 dbSNP (build 138), 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
Hartz, P. A. Personal Communication. Baltimore, Md. 11/21/2016.
Jerber, J., Zaki, M. S., Al-Aama, J. Y., Rosti, R. O., Ben-Omran, T., Dikoglu, E., Silhavy, J. L., Caglar, C., Musaev, D., Albrecht, B., Campbell, K. P., Willer, T., Almuriekhi, M., Caglayan, A. O., Vajsar, J., Bilguvar, K., Ogur, G., Abou Jamra, R., Gunel, M., Gleeson, J. G. Biallelic mutations in TMTC3, encoding a transmembrane and TPR-containing protein, lead to cobblestone lissencephaly. Am. J. Hum. Genet. 99: 1181-1189, 2016. [PubMed: 27773428] [Full Text: https://doi.org/10.1016/j.ajhg.2016.09.007]
Racape, M., Duong Van Huyen, J.-P., Danger, R., Giral, Ml, Bleicher, F., Foucher, Y., Pallier, A., Pilet, P., Tafelmeyer, P., Ashton-Chess, J., Dugast, E., Pettre, S., Charreau, B., Soulillou, J.-P., Brouard, S. The involvement of SMILE/TMTC3 in endoplasmic reticulum stress response. PLoS One 6: e19321, 2011. Note: Electronic Article. [PubMed: 21603654] [Full Text: https://doi.org/10.1371/journal.pone.0019321]
Yun, E. J., Vu, T. H. mSmile is necessary for bronchial smooth muscle and alveolar myofibroblast development. Anat. Rec. (Hoboken) 295: 167-176, 2012. [PubMed: 21956870] [Full Text: https://doi.org/10.1002/ar.21475]