Early onset dystonia

Gene: ACTB

Comment on list classification: Based on the green rating for this gene on https://panelapp.genomicsengland.co.uk/panels/847/gene/ACTB/ and review from Eldar Dedic.

Created: 9 Dec 2021, 5:02 p.m. | Last Modified: 9 Dec 2021, 5:02 p.m.

Panel Version: 1.102

Green List (high evidence)

Freitas, et al. (2020, PMID: 31970217) presented 52 years of age Brazilian female case with dystonia (onset at age of 25 years) who had additional clinical features (but without facial dysmorphism and brain abnormalities). Whole-exome-sequencing showed the presence of ACTB c.547C>T (p.Arg183Trp) variant. This variant was absent from gnomAD v2.1.1 as of December 2021.

Skogseid, et al. (2018, PMID: 29788902) presented 23 years old female case with dystonia (age at onset 13 years), mild dysmorphic facial traits and additional clinical features (but with grossly maintained brain structure). Whole-exome-sequencing revealed heterozygous ACTB c.547C>T (p.Arg183Trp) variant. The case was negative for the aCGH analysis.

Zech, et al. (2017, PMID: 28849312) presented 9 unrelated cases with combined and/or complex dystonia (8 of European and 1 of Asian origin). Whole-exome-sequencing revealed de novo ACTB c.547C>T (p.Arg183Trp) variant in 39-years-old Czech male case with complex dystonia (age of onset at 24 years) who had additional clinical features (but with normal brain MRI). The variant absence in parents has been confirmed through Sanger sequencing.

Eggink, et al. (2017, PMID: 27862284) presented a family with dystonia. Whole-exome-sequencing revealed ACTB c.547C>T (p.Arg183Trp) variant in 2 family members: 22 years old female with dystonia (age of onset at 19 years) who in addition to other clinical features showed high-arched eyebrows (but with normal brain MRI results); her 49 years old mother with dystonia (who at age 16 experienced hands trembling, at age 21 she had writer’s cramp diagnosed) and additional clinical features.

Cuvertino, et al. (2017, PMID: 29220674) analyzed data of more than 15,000 suspected genetic development disorder individuals, 26 cases with 7p22.1 deletions and 4,293 trios from the Deciphering Developmental Disorders study. The ACTB c.1097dupG (p.Ser368Leufs*13) variant has been found de novo in 12 years old heterozygous male case (of United Kingdom origin; Table S1) who had dystonia (as well as additional clinical features; Table 1). This variant was absent from gnomAD v2.1.1 as of December 2021.

- Please note that ACTB c.1097dupG (p.Ser368Leufs*13) putatively results in protein extension

Hundt, et al. (2014, PMID: 25255767) presented in vitro functional study on Sf9 cells. The results showed that ACTB c.547C>T (p.Arg183Trp) variant resulted in 3 times higher inhibition of DNase I-mediated nucleic acid cleavage (p < 0.0001; Fig.2A), unchanged thermal stability (Fig. 2B), nucleotide exchange from actin monomer was 2.4 times slower (p = 0.0113; Fig.3), 1.9 times faster half-time polymerization (p = 0.0006; Fig. 4A), 1.7 times higher ATP turnover (Fig. 4B), significantly reduced half-time of the depolymerization (Fig. 4C), close to normal binding to the profilin II (Fig. 5A), 4 times lower ability to activate ATPase of nonmuscle myosin-2A isoform (Fig. 6), in comparison to the wild-type. The authors also carried out the computational analysis and showed that this variant impaired the opening of the nucleotide cleft (Fig. 7C, Fig. 8B).

Created: 5 Dec 2021, 6:12 a.m. | Last Modified: 5 Dec 2021, 6:12 a.m.

Panel Version: 1.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• PMID: 31970217
• 29788902
• 28849312
• 27862284
• 29220674
• 25255767

Mode of pathogenicity
Other