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. 2019 Feb 11;14(1):38.
doi: 10.1186/s13023-019-1020-x.

The Mutational and Phenotypic Spectrum of TUBA1A-associated Tubulinopathy

Free PMC article

The Mutational and Phenotypic Spectrum of TUBA1A-associated Tubulinopathy

Moritz Hebebrand et al. Orphanet J Rare Dis. .
Free PMC article


Background: The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.

Results: In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.

Conclusions: With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

Keywords: Brain malformation; Developmental delay; Human phenotype ontology; Lissencephaly; Microcephaly; TUBA1A; Tubulin; Tubulinopathy.

Conflict of interest statement

Ethics approval and consent to participate

Informed written consent was obtained for all participants. The study was approved by the Ethical Committee of the Medical Faculty of the Friedrich-Alexander-Universität Erlangen-Nürnberg (180_15Bc).

Consent for publication

Informed written consent for publication was obtained for all participants.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Fig. 1
Fig. 1
Distribution and computational scores of TUBA1A variants. a TUBA1A domains and localization of variants (missense variants in red, truncating variants in black). Variants above protein scheme are from published data in PubMed, below from databases (ClinVar, DECIPHER, denovo-db). Variants reported ≥3 times (green) and from the cases reported here (blue). While the size of the circle is proportional to the reported frequency, the height is proportional to the CADD-score. b Density plot of all missense variants (pathogenic in red, present in gnomAD in blue). The dashed highlighted grey box indicates the region around Arg402 with significant clustering of pathogenic variants (see Additional file 1: Figure S5). c Generalized additive models of the CADD, M-CAP and REVEL scores for all possible missense variants (see also Additional file 1: Figure S4 A). d Violin- and scatter-plot comparing the three computational scores for missense variants found in two clinical groups of individuals (“clinical review”: 104 cases from literature review and the three cases reported here for a total of 62 distinct variants; “database”: 59 individuals from ClinVar, denovo-db and DECIPHER for a total of 59 variants), healthy controls (“gnomAD”: 9 variants) and all other possible missense variants (“simulated”: 2841 variants) (see also Additional file 1: Figure S4 B)
Fig. 2
Fig. 2
Mapping of reported variants onto 3D structure of tubulin alpha-1A. a TUBA1A (light blue) monomer in the center surrounded by TUBA1A monomers to the lateral sides and TUBB3 monomers to the longitudinal sides (transparent surfaces). The TUBA1A (light blue) - TUBB3 (grey) heterodimer is highlighted and shown in ribbon representation (based on PDB: 5JCO [28]). Exemplary for a motor protein KIF1A (green; PDB: 2HXF [73]) is shown interacting on the external surface. Mutated residues are shown in spheres and likely affect the binding of MAPs or motor proteins (red), tubulin folding (black), intradimer interactions (yellow), longitudinal interactions (magenta), lateral interactions (green) or GTP-binding pocket (beige). Variants on the luminal side are shown in blue. A cross section and longitudinal view of a microtubule [74] is provided for orientation. b Close-up view of the central TUBA1A monomer and c lateral-view with TUBB3 removed from the dimer. The GTP molecule (beige), required for polymerization, is presented in stick representation. Variants identified in the three individuals i084n (P173L), i085n (G436D), i086n (R214H) described here affect tubulin folding, MAP binding and intradimer interaction, respectively. d Simplified representation of TUBA1A and KIF1A with protein surface and spheres removed. The amino acid residue R402 (red stick representation) of TUBA1A is localized near the KIF1A protein, in particular to the amino acid residue K280 (minimal distance 1.9 Å; green stick representation)
Fig. 3
Fig. 3
Genotype-phenotype analysis. a Different colors indicate the functional class of the amino acid residue in structural model (legend 1). Different symbols indicate the PubMed identifier (PMID) of publications describing ≥5 individuals (legend 2). Individuals described here or in the literature are sorted on the x-axis by variant functional class, localization and publication. On the y-axis phenotype categories with at least 60% data availability are presented (see also Additional file 1: Figure S7). Grey highlighted boxes indicate variants at the same amino acid position (also labeled) and boxes with dashed lines indicate related individuals with the same variant. b Mosaic plots showing the relations between individual groups (fetuses, born), variant structural function (MAP_binding = “MB”, Tubulin_folding = “TF”, Lumen_facing = “LF”, Intradimer_interaction = “II”, Longitudinal_interaction = “LoI”, Lateral_interaction = “LaI”, GTP_binding = “GB”) and sex of the individual (female = f, male = m). c Association plot showing the relation between recurrently affected amino-acid positions (recurrent_AA) and the neuroradiological feature of cortical gyration (pachygyria = “Pg”, polymicrogyria = “PMG”, perisylvian polymicrogyria = “PsPMG”, cortical gyral simplification = “CgS”, agyria = “Ag”, other = “O”, absent = “a”). This example (see Additional file 1: Figure S8) indicates a possible genotype-phenotype correlation for certain recurrent variants. d Association plot showing the relation between publications describing ≥5 individuals (“pubmed_ID”) and the neuroradiological feature of cortical gyration. This example (see also Additional file 1: Figure S9) indicates a probable reporting bias for this clinical feature. Two-sided Fisher’s exact test has been used to estimate the presented p-values

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