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Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia.

ABSTRACT: Germline mutations in the ubiquitously expressed ACTB, which encodes ?-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fibroblasts, we demonstrate cohort specific changes to ?-CYA filament populations, which include the enhanced recruitment of thrombocytopenia-associated actin binding proteins (ABPs). These perturbed interactions are supported by in silico modeling and are validated in disease-relevant thrombocytes. Co-examination of actin and microtubule cytoskeleton constituents in patient-derived megakaryocytes and thrombocytes indicates that these ?-CYA mutations inhibit the final stages of platelet maturation by compromising microtubule organization. Our results define an ACTB-associated clinical syndrome with a distinct genotype-phenotype correlation and delineate molecular mechanisms underlying thrombocytopenia in this patient cohort.

SUBMITTER: Latham SL

PROVIDER: S-EPMC6185941 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia.

Latham Sharissa L SL Ehmke Nadja N Reinke Patrick Y A PYA Taft Manuel H MH Eicke Dorothee D Reindl Theresia T Stenzel Werner W Lyons Michael J MJ Friez Michael J MJ Lee Jennifer A JA Hecker Ramona R Frühwald Michael C MC Becker Kerstin K Neuhann Teresa M TM Horn Denise D Schrock Evelin E Niehaus Indra I Sarnow Katharina K Grützmann Konrad K Gawehn Luzie L Klink Barbara B Rump Andreas A Chaponnier Christine C Figueiredo Constanca C Knöfler Ralf R Manstein Dietmar J DJ Di Donato Nataliya N

Nature communications 20181012 1

Germline mutations in the ubiquitously expressed ACTB, which encodes β-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fib ...[more]

PMID: 30315159

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Project description:The current study elucidated an association between gene variants and thrombocytopenia through the investigation of the exonic polymorphic landscape of hematopoietic transcription factor-GATA1 gene in dengue patients. A total of 115 unrelated dengue patients with dengue fever (DF) (N = 91) and dengue hemorrhagic fever (DHF) (N = 24) were included in the study. All dengue patients were confirmed through detection of NS1 antigen, IgM, and IgG antibodies against the dengue virus. Polymerase chain reaction using specific primers amplified the exonic regions of GATA1 while Sanger sequencing and chromatogram analyses facilitated the identification of variants. Variants G>A (at chX: 48792009) and C>A (at chX: 4879118) had higher frequency out of 13 variants identified (3 annotated and 10 newly recognized). Patients carrying either nonsynonymous or synonymous variants had significantly lower mean values of platelets compared to those harboring the reference nucleotides (NC_000023.11). Further analyses revealed that the change in amino acid residue leads to the altered three-dimensional structure followed by interaction with neighboring residues. Increased stability of the protein due to substitution of serine by asparagine (S129N at chX: 48792009) may cause increased rigidity followed by reduced structural flexibility which may ultimately disturb the dimerization (an important prerequisite for GATA1 to perform its biological activity) process of the GATA1 protein. This, in turn, may affect the function of GATA1 followed by impaired production of mature platelets which may be reflected by the lower platelet counts in individuals with such variation. In summary, we have identified new variants within the GATA1 gene which were found to be clinically relevant to the outcome of dengue patients and thus, have the potential as candidate biomarkers for the determination of severity and prognosis of thrombocytopenia caused by dengue virus. However, further validation of this study in a large number of dengue patients is warranted. Trial Registration: number SLCTR/2019/037.

Dataset Information

Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia.

Publications

Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia.

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