Alternative titles; symbols
HGNC Approved Gene Symbol: TBC1D20
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:435,480-462,533 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | Warburg micro syndrome 4 | 615663 | Autosomal recessive | 3 |
Sklan et al. (2007) used a 2-hybrid screen to isolate proteins that bind with the hepatitis C virus (HCV) nonstructural protein NS5A. One such protein, TBC1D20, contains a TBC (Tre2, Bub2, and Cdc16) domain found in most Rab-GTPase-activating proteins (GAPs), which are important in vesicular membrane transport. Immunoprecipitation of tagged TBC1D20 showed that the precipitate included HCV NS5A, confirming the interaction. Deletion experiments mapped the interaction domain with NS5A to the C-terminal domain of TBC1D20.
Scott (2007) mapped the TBC1D20 gene to chromosome 20p13 based on an alignment of the TBC1D20 sequence (GenBank AL121747) with the genomic sequence (build 36.2).
Sklan et al. (2007) showed that reduction of TBC1D20 expression by siRNA severely impaired HCV replication and inhibited new infection. The authors noted that the interaction of HCV with TBC1D20, a protein that may mediate endocytosis, trafficking, and sorting of cellular proteins, represents a new mechanism by which viruses could subvert the host cell and that this insight may offer a new route for pharmacologic intervention.
Sklan et al. (2007) showed that TBC1D20 colocalized with calnexin (114217) in the endoplasmic reticulum, which led them to investigate Rabs associated with the ER as possible targets of TBC1D20. They identified RAB1 (179508) as the GTPase activated by TBC1D20.
In a cohort of 77 patients with a spectrum of eye, brain, and endocrine abnormalities, all of whom were negative for mutation in the known Warburg Micro syndrome genes RAB3GAP1 (602536), RAB3GAP2 (609275), and RAB18 (602207), Liegel et al. (2013) analyzed the candidate gene TBC1D20 and identified homozygous mutations in 7 patients with typical features of Warburg Micro syndrome (WARBM4; 615663) from 5 families of different ethnic origins (611663.0001-611663.0005).
In 3 Egyptian sibs, born to consanguineous parents, with WARBM4, Abdel-Hamid et al. (2020) identified homozygosity for the R67X mutation in the TBC1D20 gene (611663.0001) that was previously identified by Liegel et al. (2013). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Varnum (1983) described mice with a recessive mutation designated 'blind-sterile' (bs). Affected adults had glossy coats and eyes that were slightly smaller than normal with bilateral lenticular cataracts. The cataracts did not enlarge with age, and the cortex of the lens was transparent and appeared normal. Affected females were fertile and produced normal-sized litters, whereas affected males, which had testes of near-normal size, did not reproduce, and the homozygous bs/bs vas deferens rarely contained sperm. Histology of bs/bs testes showed normal spermatogonia, spermatocysts, and primary spermatids, but spermatogenesis appeared to stop after formation of the spermatid, with only a few areas of condensed nuclear material or a few poorly formed sperm heads observed. Inheritance data were consistent with bs as a recessive autosomal mutation with good penetrance, and showed that it was located on mouse chromosome 2 near agouti (see 600201).
Liegel et al. (2013) studied bs mice and observed that lens abnormalities appeared at embryonic day (E) 17.5, at which time lenses appeared smaller in size and exhibited degenerated nuclear fibers with small vacuoles between cortical fibers. By postnatal day (P) 10, the bs lens phenotype was characterized by severely degenerated TUNEL(+) nuclear fiber cells, and by P28, severe lens degeneration with large vacuoles was present throughout the lens body, accompanied by rupture of the lens capsule and lenticular material in the vitreous cavity. Liegel et al. (2013) concluded that bs cataracts are associated with a defect in lens fiber cell maturation with an embryonic onset. In addition, adult bs testes were significantly smaller than wildtype, and exhibited significant depletion of germ cells. Peanut agglutinin (PNA) staining confirmed the previously reported failure of acrosome formation in bs spermatids. Evaluation of mouse embryonic fibroblasts showed enlarged Golgi morphology and aberrant lipid droplet formation. Given the severe brain abnormalities observed in patients with TBC1D20 mutations, Liegel et al. (2013) evaluated brains from bs mice, but identified no obvious morphologic abnormalities.
In 2 Polish sibs with Warburg Micro syndrome (WARBM4; 615663), Liegel et al. (2013) identified homozygosity for a c.199C-T transition in exon 2 of the TBC1D20 gene, resulting in an arg67-to-ter (R67X) substitution. The unaffected parents were heterozygous for the mutation, which was not found in the Exome Variant Server database (ESP6500SI-V2) or in 200 controls.
In 3 Egyptian sibs, born to consanguineous parents, with WARBM4, Abdel-Hamid et al. (2020) identified homozygosity for the R67X mutation in the TBC1D20 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
In a 6-year-old Dutch girl with Warburg Micro syndrome (WARBM4; 615663), Liegel et al. (2013) identified homozygosity for a c.292C-T transition in exon 3 of the TBC1D20 gene, resulting in a gln98-to-ter (Q98X) substitution. The unaffected parents were heterozygous for the mutation, which was not found in the Exome Variant Server database (ESP6500SI-V2) or in 200 controls.
In 2 Pakistani sisters with Warburg Micro syndrome (WARBM4; 615663), Liegel et al. (2013) identified homozygosity for a 2-bp deletion (c.352_353delCA) in exon 4 of the TBC1D20 gene, causing a frameshift predicted to result in the addition of 9 novel amino acids and a premature termination codon (Gln118GlufsTer9). The unaffected parents were heterozygous for the mutation, which was not found in the Exome Variant Server database (ESP6500SI-V2) or in 200 controls.
In a 14-year-old Egyptian boy with Warburg Micro syndrome (WARBM4; 615663), Liegel et al. (2013) identified homozygosity for a c.672G-A transition in exon 6 of the TBC1D20 gene, resulting in a trp224-to-ter (W224X) substitution. The unaffected parents were heterozygous for the mutation, which was not found in the Exome Variant Server database (ESP6500SI-V2) or in 200 controls.
In a 15-year-old Pakistani girl with Warburg Micro syndrome (WARBM4; 615663), Liegel et al. (2013) identified homozygosity for a microdeletion encompassing exons 2 through 8 of the TBC1D20 gene. The mutation, which was confirmed by quantitative PCR, was not found in the Exome Variant Server database (ESP6500SI-V2) or in 200 controls. Parental DNA was not available.
Abdel-Hamid, M. S., Abdel-Ghafar, S. F., Ismail, S. R., Desouky, L. M., Issa, M. Y., Effat, L. K., Zaki, M. S. Micro and Martsolf syndromes in 34 new patients: refining the phenotypic spectrum and further molecular insights. Clin. Genet. 98: 445-456, 2020. [PubMed: 32740904] [Full Text: https://doi.org/10.1111/cge.13825]
Liegel, R. P., Handley, M. T., Ronchetti, A., Brown, S., Langemeyer, L., Linford, A., Chang, B., Morris-Rosendahl, D. J., Carpanini, S., Posmyk, R., Harthill, V., Sheridan, E., and 11 others. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg Micro syndrome in humans. Am. J. Hum. Genet. 93: 1001-1014, 2013. [PubMed: 24239381] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.011]
Scott, A. F. Personal Communication. Baltimore, Md. 12/12/2007.
Sklan, E. H., Serrano, R. L., Einav, S., Pfeffer, S. R., Lambright, D. G., Glenn, J. S. TBC1D20 is a Rab1 GTPase-activating protein that mediates hepatitis C virus replication. J. Biol. Chem. 282: 36354-36361, 2007. [PubMed: 17901050] [Full Text: https://doi.org/10.1074/jbc.M705221200]
Sklan, E. H., Staschke, K., Oakes, T. M., Elazar, M., Winters, M., Aroeti, B., Danieli, T., Glenn, J. S. A Rab-GAP TBC domain protein binds hepatitis C virus NS5A and mediates viral replication. J. Virol. 81: 11096-11105, 2007. [PubMed: 17686842] [Full Text: https://doi.org/10.1128/JVI.01249-07]
Varnum, D. S. Blind-sterile: a new mutation on chromosome 2 of the house mouse. J. Hered. 74: 206-207, 1983. [PubMed: 6863898] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a109768]