Alternative titles; symbols
HGNC Approved Gene Symbol: TUBGCP2
Cytogenetic location: 10q26.3 Genomic coordinates (GRCh38) : 10:133,278,635-133,312,337 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.3 | Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures | 618737 | Autosomal recessive | 3 |
The gamma-tubulin (TUBG; see 605785) ring complex is a microtubule-organizing center that acts as a template for polarized growth of microtubules essential for diverse cellular structures. The TUBG small complex, a component of the ring complex, consists of multimers of TUBGCP2, TUBGCP3 (617818), and TUBG and is the immediate template for growing microtubule ends (Riehlman et al., 2013).
By searching an EST database for sequences similar to yeast Spc97, followed by PCR of a HeLa cell cDNA library, Murphy et al. (1998) cloned TUBGCP2, which they called GCP2. GCP2 has 5 domains that are conserved with human GCP3 (TUBGCP3) and their respective yeast orthologs, Spc97 and Spc98. GCP2 has a predicted molecular mass of 103 kD. Immunohistochemical analysis showed colocalization of GCP2 and GCP3 with TUBG at centrosomes. Following expression in insect cells, GCP2 and GCP3 ran as a tight doublet at an apparent molecular mass of approximately 100 kD. Database analysis detected orthologs of GCP2 in mouse, Drosophila, and moss.
By coimmunoprecipitation analysis, Murphy et al. (1998) found that epitope-tagged human TUBG interacted with endogenous Gcp2 and Gcp3 in mouse 3T3 embryonic fibroblasts. Sucrose gradient fractionation of human 293 cells detected GCP2 and GCP3 in the same fraction with TUBG. The complex had a sedimentation coefficient of 32S. Both GCP2 and GCP3 sedimented with stabilized microtubules, and depolymerization of microtubules had no effect on association of GCP2 with GCP3 and TUBG.
Riehlman et al. (2013) found that human GCP3, but not GCP2, assembled into a fission yeast TUBG ring complex of over 2 MDa. GCP3 replaced yeast Alp6 (Spc98) in the complex and rescued growth in yeast expressing a fatal Alp6 mutant. In contrast, GCP2 predominantly assembled into a smaller TUBG complex and was unable to rescue yeast expressing defective Alp4 (Spc97). Generation of Alp4-GCP2 chimeras revealed that the GCP2 N-terminal domain limited its ability to replace Alp4 during TUBG ring complex assembly.
Hartz (2017) mapped the TUBGCP2 gene to chromosome 10q26.3 based on an alignment of the TUBGCP2 sequence (GenBank AF042379) with the genomic sequence (GRCh38).
In 5 patients from 4 families with complex cortical dysplasia with other brain malformations-15 (CDCBM15; 618737), Mitani et al. (2019) identified homozygous or compound heterozygous mutations in the TUBGCP2 gene (617817.0001-617817.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. The patients were ascertained through collaborative efforts and GeneMatcher. Functional studies of the variants were not performed, but analysis of patient fibroblasts derived from 1 patient with a splice site mutation demonstrated the production of several abnormal transcripts that were predicted to result in a loss of function. The 3 other variants, all missense, occurred at highly conserved residues in the important Grip1 and Grip2 (621438) functional domains. The authors hypothesized that the role of TUBGCP2 in microtubules could explain the abnormality in neuronal migration observed in these patients.
In 2 sibs with CDCBM15, who were born to first-cousin Turkish parents, Gungor et al. (2021) identified a homozygous mutation in the TUBGCP2 gene (E311K; 617817.0005). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents and a healthy sib; it was not present in the gnomAD database or in a cohort of 1,182 Turkish controls. The variant, which is predicted to disrupt the electrostatic interaction between the GCP2 and GCP3 proteins, was shown not to affect GCP2 protein levels, but a delocalization of gamma-tubulin was noted. Using mass spectrometry, dysregulation of multiple proteins that are important to the development and maintenance of the nervous system was noted. Gungor et al. (2021) stated that these results suggest that axon and neurite outgrowth/elongation might also be altered, along with perturbed neuronal differentiation, migration, and synaptic plasticity. In addition, the results could explain the findings of brainstem atrophy and disturbed myelination seen in some patients as well as abnormalities in neuronal migration.
In 2 affected boys from a highly consanguineous multigenerational Turkish family (family 1) with complex cortical dysplasia with other brain malformations-15 (CDCBM15; 618737), Mitani et al. (2019) identified a homozygous c.997C-T transition (c.997C-T, NM_006659.1) in exon 7 of the TUBGCP2 gene, resulting in an arg333-to-cys (R333C) substitution at a highly conserved residue in the Grip1 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. One of the boys had seizures and the other did not. One of the patients, who had a more severe phenotype with some additional features, including broad toes, widely spaced teeth, and autistic behavior, also carried a de novo duplication of 2q23.1 (see 156200).
In 2 unrelated girls, 1 born of unrelated Indian parents (family 2) and the other of consanguineous Iranian parents (family 3), with complex cortical dysplasia with other brain malformations-15 (CDCBM15; 618737), Mitani et al. (2019) identified a homozygous c.1843G-C transversion (c.1843G-C, NM_006659.1) in exon 12 of the TUBGCP2 gene, resulting in an ala615-to-pro (A615P) substitution at a conserved residue in the Grip2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Both patients were born prematurely and died at 3 years of age.
In a 4-year-old boy, born of unrelated Polish parents (family 4), with complex cortical dysplasia with other brain malformations-15 (CDCBM15; 618737), Mitani et al. (2019) identified compound heterozygous mutations in the TUBGCP2 gene: a c.889C-T transition (c.889C-T, NM_006659.1) in exon 7, resulting in an arg297-to-cys (R297C) at a highly conserved residue in the Grip1 domain, and an A-to-G transition in intron 13 (c.2025-2A-G; 617817.0004), resulting in the production of several aberrant transcripts that was demonstrated by RT-PCR analysis of patient cells. The transcripts were predicted to result in nonsense-mediated mRNA decay or production of a truncated protein lacking part of the Grip2 domain. Both scenarios would lead to a loss of function. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed. Seizures were not reported, but EEG of the patient showed paroxysmal epileptiform activity localized to the central area.
For discussion of the A-to-G transition in intron 13 of the TUBGCP2 gene (c.2025-2A-G, NM_006659.1) that was found in compound heterozygous state in a patient with complex cortical dysplasia with other brain malformations-15 (CDCBM15; 618737) by Mitani et al. (2019), see 617817.0003.
In 2 sibs, born to first-cousin Turkish parents, with complex cortical dysplasia with other brain malformations-15 (CDCBM15; 618737), Gungor et al. (2021) identified homozygosity for a G-A transition in the TUBGCP2 gene, resulting in a glu311-to-lys (E311K) substitution in the GCP2 protein. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents and a healthy sib; it was not present in the gnomAD database or in a cohort of 1,182 ethnically matched Turkish controls. (In the article by Gungor et al. (2021), the nucleotide change is stated as c.1015G-A in tables 1 and 2 but as c.931G-A in figure 1 and in the text.)
Gungor, S., Oktay, Y., Hiz, S., Aranguren-Ibanez, A., Kalafatcilar, I., Yaramis, A., Karaca, E., Yis, U., Sonmezler, E., Ekinci, B., Aslan, M., Yilmaz, E., and 12 others. Autosomal recessive variants in TUBGCP2 alter the gamma-tubulin ring complex leading to neurodevelopmental disease. iScience 24: 101948, 2021. [PubMed: 33458610] [Full Text: https://doi.org/10.1016/j.isci.2020.101948]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/18/2017.
Mitani, T., Punetha, J., Akalin, I., Pehlivan, D., Dawidziuk, M., Akdemir, Z. C., Yilmaz, S., Aslan, E., Hunter, J. V., Hijazi, H., Grochowski, C. M., Jhangiani, S. N., and 25 others. Bi-allelic pathogenic variants in TUBGCP2 cause microcephaly and lissencephaly spectrum disorders. Am. J. Hum. Genet. 105: 1005-1015, 2019. [PubMed: 31630790] [Full Text: https://doi.org/10.1016/j.ajhg.2019.09.017]
Murphy, S. M., Urbani, L., Stearns, T. The mammalian gamma-tubulin complex contains homologues of the yeast spindle pole body components Spc97p and Spc98p. J. Cell Biol. 141: 663-674, 1998. [PubMed: 9566967] [Full Text: https://doi.org/10.1083/jcb.141.3.663]
Riehlman, T. D., Olmsted, Z. T., Branca, C. N., Winnie, A. M., Seo, L., Cruz, L. O., Paluh, J. L. Functional replacement of fission yeast gamma-tubulin small complex proteins Alp4 and Alp6 by human GCP2 and GCP3. J. Cell Sci. 126: 4406-4413, 2013. [PubMed: 23886939] [Full Text: https://doi.org/10.1242/jcs.128173]