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. 2023 Oct;270(10):5057-5063.
doi: 10.1007/s00415-023-11816-w. Epub 2023 Jul 7.

A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A

Annalaura Torella  1   2 , Ivana Ricca  3 , Giulio Piluso  1 , Daniele Galatolo  3 , Giuseppe De Michele  4 , Mariateresa Zanobio  1 , Rosanna Trovato  3 , Giovanna De Michele  4 , Roberta Zeuli  1 , Chiara Pane  4 , Sirio Cocozza  5 , Francesco Saccà  4 , Filippo M Santorelli  3 , Vincenzo Nigro  1   2 , Alessandro Filla  6
Affiliations

A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A

Annalaura Torella et al. J Neurol. 2023 Oct.

Abstract

Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and β-tubulins, the structural components of microtubules. Less frequently, mutations in tubulins may underlie neurodegenerative disorders. In the present study, we report two families, one with 11 affected individuals and the other with a single patient, carrying a novel, likely pathogenic, variant (p. Glu415Lys) in the TUBA4A gene (NM_006000). The phenotype, not previously described, is that of spastic ataxia. Our findings widen the phenotypic and genetic manifestations of TUBA4A variants and add a new type of spastic ataxia to be taken into consideration in the differential diagnosis.

Keywords: Spastic ataxia; TUBA4A; Tubulinopathy.

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Conflict of interest statement

The authors declare that they do not have conflicts of interest.

Figures

Fig. 1
Fig. 1
A Pedigrees of Families 1 and 2. B In silico evaluations of the missense variant p.Glu415Lys identified in the two families. Data suggest that the mutation is harmful to normal protein function. TUBA4A protein modeling of the novel mutation was carried out using the HOPE webserver (https://www3.cmbi.umcn.nl/hope/), which analyzes structural effects of missense mutations retrieving information related to the amino acid sequence and a calculation of the three-dimensional protein structure (using modeling webtools as in [21]). The side chains of wild-type and mutated residues are in dark gray and are also represented as sticks alongside the surrounding residues, which are involved in any type of interaction. Calculation of differential stabilizing energy using the AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk) shows that the replacement of lysine for glutamic acid at residue 415 likely leads to a destabilizing effect. C Patient IV.5, age 29 years: Coronal T2-weighted MRI showing hyperintensity of the dentate (white arrow) and possible enlargement of the interfolial spaces in the crus I–II
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