Non-muscular actinopathies: Baraitser-Winter Cerebrofrontofacial syndrome and related disorders
Final Report Abstract
ACTB and ACTG1 encode the cytoskeletal beta- and gamma-actin isoforms. The reasons for the great diversity of disease patterns caused by mutations in these ubiquitously expressed genes have so far remained poorly understood. We compiled and analyzed data from 270 individuals with putative pathogenic ACTB/ACTG1 variants. The resulting findings show that ACTB pLOF SNVs or small deletions tend to cause a mild neurodevelopmental-malformation syndrome; ACTG1 pLOF SNVs or small deletions are either benign or increase susceptibility for neurodevelopmental problems; ACTB missense/in-frame variants (MVs) cause Baraitser-Winter-Cerebrofrontofacial syndrome (ACTB- related BWCFFS) or dystonia-deafness syndrome (a single recurrent MV) or a disorder that is phenotypically similar to that caused by pLOF ACTB variants; ACTG1 MVs cause ACTG1-related BWCFFS or isolated deafness or likely isolated colobomas. Furthermore, a set of pathogenic ACTB/ACTG1 variants remained phenotypically unclassified. Expression studies in cells from patients with ACTB pLOF variants showed normal levels of ACTB but significant upregulation of ACTA2, suggesting that the underlying mechanism is mediated by impaired transcriptional adaptation. Biochemical studies showed that most ACTB/ACTG1 MVs interfere with actin polymerization/ depolymerization and/or disrupt actin-myosin interactions, suggesting dominant negative effects. Some ACTB MVs causing a ‘ACTB-pLOF phenotype’ resulted in protein degradation, suggesting functional haploinsufficiency as the underlying disease mechanism. Mice with BWCCFS variants were embryonic lethal. We have defined at least eight diseases caused by ACTB/ACTG1 variants and outlined their putative genotype-disease relationships. We propose to group these diseases together as "non-muscle actinopathies". Our findings shed light on the diversity of mechanisms underlying the non-muscle actinopathies and provide a strong basis for the development of new therapeutic approaches.
Publications
- Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia. Nat Commun. 2018 Oct 12;9(1):4250
Latham S.L., Ehmke N., Reinke P.Y.A., Taft M.H., Eicke D., Reindl T., Stenzel W., Lyons M.J., Friez M.J., Lee J.A,. Hecker R., Frühwald M.C., Becker K., Neuhann T.M, Horn D., Schrock E., Niehaus I., Sarnow K., Grützmann K., Gawehn L., Klink B., Rump A., Chaponnier C., Figueiredo C., Knöfler R., Manstein D.J., Di Donato N.
(See online at https://doi.org/10.1038/s41467-018-06713-0) - Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia. Nat Commun. 2018 Oct 12;9(1):4250. Erratum in: Nat Commun. 2018 Nov 19;9(1):4930
Latham SL, Ehmke N, Reinke PYA, Taft MH, Eicke D, Reindl T, Stenzel W, Lyons MJ, Friez MJ, Lee JA, Hecker R, Frühwald MC, Becker K, Neuhann TM, Horn D, Schrock E, Niehaus I, Sarnow K, Grützmann K, Gawehn L, Klink B, Rump A, Chaponnier C, Figueiredo C, Knöfler R, Manstein DJ, Di Donato N
(See online at https://doi.org/10.1038/s41467-018-06713-0 https://doi.org/10.1038/s41467-018-07404-6) - Dermatological signs lead to discovery of mosaic ACTB variants in segmental odontomaxillary dysplasia. Br J Dermatol. 2020 Dec;183(6):1128-1130
Polubothu S, Abdin D, Barysch M, Thomas A, Bulstrode N, Evans R, Solman L, Obwegeser J, Hennekam RC, Weibel L, Calder A, Di Donato N, Kinsler VA
(See online at https://doi.org/10.1111/bjd.19339) - (2021) Allosteric modulation of cardiac myosin mechanics and kinetics by the conjugated omega-7,9 trans-fat rumenic acid. J.Physiol.
Pertici, I., Taft, M.H., Greve, J.N., Fedorov, R., Caremani, M., Manstein, D.J.
(See online at https://doi.org/10.1113/jp281563) - (2021) Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation MYBPC3D25bp/D389V. Int. J.Mol. Sci.
Schwäbe, F.V., Peter, E.K., Taft, M.H., Manstein, D.J.
(See online at https://doi.org/10.3390/ijms222111949) - (2021) CORE-MD II: A fast, adaptive and accurate enhanced sampling method. J. Chem. Phys.
Peter, E.K., Manstein, D.J., Shea, J.E., Schug, A.
(See online at https://doi.org/10.1063/5.0063664) - Update on diagnostics and clinical management. European Journal of Paediatric Neurology, 2021, 35, pp. 147–152
Koenig, M., Dobyns, W.B., Di Donato, N. Lissencephaly
(See online at https://doi.org/10.1016/j.ejpn.2021.09.013) - (2022) Distinct actin-tropomyosin cofilament populations drive the functional diversification of cytoskeletal myosin motor complexes. iScience
Reindl T., Giese S., Greve J.N., Reinke P.Y., Chizhov I., Latham S.L., Mulvihill D.P., Taft M.H., Manstein D.J.
(See online at https://doi.org/10.1016/j.isci.2022.104484) - (2022) Frameshift mutation S368fs in the gene encoding cytoskeletal β-actin leads to ACTB-associated syndromic thrombocytopenia by impairing actin dynamics. Eur J Cell Biol.
Greve J.N., Schwäbe F.V., Pokrant T., Faix J., Di Donato N., Taft M.H., Manstein D.J.
(See online at https://doi.org/10.1016/j.ejcb.2022.151216) - (2022) Frameshift mutation S368fs in the gene encoding cytoskeletal β-actin leads to ACTB-associated syndromic thrombocytopenia by impairing actin dynamics. Eur J Cell Biol.
Greve J.N., Schwäbe F.V., Pokrant T., Faix J., Di Donato N., Taft M.H., Manstein D.J.
(See online at https://doi.org/10.1016/j.ejcb.2022.151216) - Baraitser-Winter Cerebrofrontofacial Syndrome. 2015 Nov 19 [Updated 2022 Mar 24]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022
Verloes A, Drunat S, Pilz D, Di Donato N
