Alternative titles; symbols
HGNC Approved Gene Symbol: TBC1D7
Cytogenetic location: 6p24.1 Genomic coordinates (GRCh38): 6:13,304,951-13,328,537 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p24.1 | Macrocephaly/megalencephaly syndrome, autosomal recessive | 248000 | Autosomal recessive | 3 |
TBC1D7 belongs to a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; 604334), yeast Bub2, and CDC16 (603461) (Nakashima et al., 2007).
Nakashima et al. (2007) identified TBC1D7, which they called TBC7, by coimmunoprecipitation with the tuberous sclerosis complex proteins TSC1 (605284) and TSC2 (191092) from transfected HEK293 cells. The deduced 293-amino acid TBC1D7 protein contains a putative TBC domain. SDS-PAGE showed that TBC1D7 was expressed as a 30-kD protein. Northern blot analysis detected an approximately 1.1-kb transcript with high expression in human heart and low expression in kidney, liver, and placenta. Immunofluorescence studies colocalized TBC1D7 and TSC1 to the cytoplasm when expressed in NIH3T3 cells; with subcellular fractionation, TBC1D7 localized to the cytoplasmic vesicles of the endomembrane in a complex with TSC1-TSC2.
By immunoblot and GST pull-down assay, Nakashima et al. (2007) confirmed that TBC1D7 interacted with the TSC1-TSC2 complex. Further studies showed that TBC1D7 interacted directly with TSC1 through the C-terminal half of the TSC1 coiled-coil domain. Overexpression of TBC1D7 caused an increase in phosphorylation of ribosomal S6 protein (RPS6; 180460) at ser235/236 by RPS6 kinase (RPS6KB1; 608938) activation, suggesting that TBC1D7 plays a role in positive regulation of the mTOR-signaling pathway. Overexpression of TBC1D7 also increased TSC1 ubiquitination.
Gross (2014) mapped the TBC1D7 gene to chromosome 6p24.1 based on an alignment of the TBC1D7 sequence (GenBank AB449888) with the genomic sequence (GRCh37).
In 2 sibs, born of consanguineous parents of North African descent, with autosomal recessive macrocephaly/megalencephaly syndrome (MGCPH; 248000) and intellectual disability, Capo-Chichi et al. (2013) identified a homozygous truncating mutation in the TBC1D7 gene (612655.0001). The mutation was found by homozygosity mapping and whole-exome sequencing. Patient cells showed no TBC1D7 mRNA or protein, consistent with nonsense-mediated mRNA decay. Patient cells showed constitutive activation of the mTORC1 complex (see 601231) compared to controls, consistent with TBC1D7 playing the role of an upstream regulator of mTORC1.
In 2 Italian sisters with macrocephaly and intellectual disability, Alfaiz et al. (2014) identified a homozygous truncating mutation in the TBC1D7 gene (612655.0002).
In 2 sibs, born of consanguineous parents of North African descent, with autosomal recessive macrocephaly/megalencephaly syndrome (MGCPH; 248000) and intellectual disability, Capo-Chichi et al. (2013) identified a homozygous 1-bp deletion (538delT) in the TBC1D7 gene, resulting in a frameshift and premature termination (Tyr180ThrfsTer1). The mutation was found by homozygosity mapping and whole-exome sequencing, and it segregated with the disorder in the family. It was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Sequencing Project databases, or in over 700 in-house exome datasets or 285 control individuals from North Africa. Patient cells showed no TBC1D7 mRNA or protein, consistent with nonsense-mediated mRNA decay. Patient cells showed constitutive activation of the mTORC1 complex (see 601231) compared to controls, consistent with TBC1D7 playing the role of an upstream regulator of mTORC1.
In 2 Italian sisters with MGCPH (248000), Alfaiz et al. (2014) identified a homozygous 4-bp deletion (c.17_20delAGAG) in the TBC1D7 gene, resulting in a frameshift and premature termination (Arg7ThrfsTer21). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed no detectable TBC1D7 protein on Western blot analysis, suggesting a loss of function. Loss of the TBC1D7 protein was associated with increased phosphorylation of 4EBP1 (602223), a downstream target of mTORC1 (see 601231). Transfection of the mutation into HEK293 cells resulted in a delay in initiation of the autophagy process, and this defect was rescued by expression of wildtype TBC1D7. The findings suggested that impaired autophagy results in the disorder. In addition to macrocrania and intellectual disability, both sisters had celiac disease, kidney oxalate stones, osteoarticular defects, and patellar subluxation.
Alfaiz, A. A., Micale, L., Mandriani, B., Augello, B., Pellico, M. T., Chrast, J., Xenarios, I., Zelante, L., Merla, G., Reymond, A. TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. Hum. Mutat. 35: 447-451, 2014. [PubMed: 24515783] [Full Text: https://doi.org/10.1002/humu.22529]
Capo-Chichi, J.-M., Tcherkezian, J., Hamdan, F. F., Decarie, J. C., Dobrzeniecka, S., Patry, L., Nadon, M.-A., Mucha, B. E., Major, P., Shevell, M., Bencheikh, B. O. A., Joober, R., Samuels, M. E., Rouleau, G. A., Roux, P. P., Michaud, J. L. Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. J. Med. Genet. 50: 740-744, 2013. [PubMed: 23687350] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101680]
Gross, M. B. Personal Communication. Baltimore, Md. 5/27/2014.
Nakashima, A., Yoshino, K., Miyamoto, T., Eguchi, S., Oshiro, N., Kikkawa, U., Yonezawa, K. Identification of TBC7 having TBC domain as a novel binding protein to TSC1-TSC2 complex. Biochem. Biophys. Res. Commun. 361: 218-223, 2007. [PubMed: 17658474] [Full Text: https://doi.org/10.1016/j.bbrc.2007.07.011]