De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Abstract

Brain malformations are individually rare but collectively common causes of developmental disabilities1–3. Many forms occur sporadically and have reduced reproductive fitness, pointing towards a causative role for de novo mutations4,5. Here we report our studies of Baraitser-Winter syndrome, a well-defined syndrome characterized by distinct craniofacial features, ocular colobomata and a neuronal migration defect6,7. By using whole-exome sequencing in three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in fifteen additional patients revealed disease-causing mutations in all probands, including two recurrent de novo mutations (ACTB p.Arg196His and ACTG1 p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover the genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actins in development, and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutations of these two genes.

Baraitser–Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

“…Mutation analysis was performed using Sanger sequencing in four laboratories (initial research in Seattle and Nijmegen, routine in Paris and Dresden). We gathered 42 patients, including the 16 patients briefly reported in our first paper, 7 four newly published patients with mutations 6,8,9 and twins with an ACTB mutation, who developed dystonia in late childhood and died in their early twenties, 10,11 as, retrospectively, the diagnosis in these patients was compatible with BWCFF (B26 and B27).…”

“…A cutaneous lymphoma was diagnosed at the age of 19 years in patient A1 (61458 in 7 and patient 3 in 8 ), with a p.Thr120Ile mutation in ACTG1. Patient B25, who carries a p.Val209Leu mutation in ACTB, developed precursor B-cell acute lymphatic leukemia (ALL) at the age of 8 years and was treated according to the Dutch Childhood Oncology Group ALL-9 high-risk group protocol.…”

“…The morphology and the F-actin organization in lymphoblastoid cell lines from BWCFF patients with different ACTB or ACTG1 mutations demonstrated distinct abnormal patterns of F-actin organization, suggesting that the morphological impact of missense mutations may differ in a mutation-specific way. 7 The in vitro and in vivo effects of single mutations have been studied for eight ACTG1 mutations causing DFNA20/26: 32,33 each mutation leads to specific alteration of the cell morphology, actin polymerization and interaction with the actin-binding proteins. An experiment with two BWCFF-associated ACTB mutations (p.Arg196His and p.Asn12Asp) confirmed mutation-specific morphological changes.…”

“…An experiment with two BWCFF-associated ACTB mutations (p.Arg196His and p.Asn12Asp) confirmed mutation-specific morphological changes. 7 Procaccio et al showed that p.Arg183Trp affects the ATP-binding pocket resulting in a more stable actin polymer, which is not depolymerized by the severing protein cofilin. This particular mutation may have a functional effect on development similar to other BWCFF variants, but may interfere specifically with another cellular process to explain the dystonia.…”

“…Winter noted: 'there does seem to be considerable overlap between the three groups [of CFF] suggesting a common embryological pathway, if not allelic mutations' . CFF3 was a heterogeneous group, encompassing several reports of [6][7][8][9] In this article, we discuss 42 patients with mutations in these genes with BWMS, FA or CFF. Having identified identical mutations in patients carrying a clinical diagnosis of BWMS, FA or CFF, we propose a unified designation: Baraitser-Winter cerebrofrontofacial syndrome (BWCFF).…”