A novel mutation in ACTG1 causing Baraitser-Winter syndrome with extremely variable expressivity in three generations

Abstract

Baraitser-Winter Syndrome (cerebro-frontofacial syndrome, type 3) is a rare developmental disorder typified by hypertelorism, ptosis, high arched eyebrows, ocular coloboma and brain malformations including lissencephaly. Other common manifestations include hearing loss, short stature, seizures, intellectual impairment and abnormalities of the kidney and urinary system. This syndrome is caused by missense mutations in the genes ACTB or ACTG1, both of which encode for cytoplasmic actin proteins crucial for proper development of many organs in the human body. We have identified a three generation pedigree segregating a novel mutation in the ACTG1 gene that leads to Baraitser-Winter Syndrome when fully expressed and isolated hearing loss when incompletely expressed.

Genes and pathways in optic fissure closure

“…This change depends on regulated contraction of the actin-myosin cytoskeleton [163,164]. Mutations in the human cytoplasmic actin genes ACTG1 and ACTB have been implicated in Baraitser-Winter syndrome which includes ocular coloboma [70,165]. Studies in medaka fish have shown that basal constriction is achieved, at least partially, through the enrichment of focal adhesions at the basal ends of cells, and the resultant basolateral transmission of stress along the epithelial sheet.…”

Acute myeloid leukemia in Baraitser–Winter cerebrofrontofacial syndrome

“…So the present patient is the third reported case of a BWCFF patient developing an hematological malignancy. At present, 52 molecularly confirmed BWCFF patients have been published [Gearing et al, ; Rivière et al, ; Johnston et al, ; Di Donato et al, , ; Eker et al, ; Poirier et al, ; Verloes et al, ; Kemerley et al, ]. Three individuals out of a total of 52 to have a haematologic malignancy is higher compared to the frequency of haematological malignancies in the general population.…”

The makings of the ‘actin code': regulation of actin's biological function at the amino acid and nucleotide level

“…Conditional γ-cytoplasmic actin knockout in the skeletal muscle results in progressive myopathy (Sonnemann et al, 2006) and affects muscle relaxation (O'Rourke et al, 2018). Seven different autosomal dominant missense mutations in the γ-actin gene have been linked to Baraitser-Winter syndrome (Kemerley et al, 2017) and progressive hearing loss in humans: T278I, T89I, K118M, P264L, P332A, I122V and V370A (Bryan et al, 2006;Liu et al, 2008;Rendtorff et al, 2006;van Wijk et al, 2003;Zhu et al, 2003). Together, these studies indicate an essential role for γ-actin in the maintenance of stereocilia, even though this actin isoform appears to be largely dispensable for the viability of an organism.…”

“…Two mutations in the human β-actin gene have been characterized: E364 K mutation, which has been correlated to neutrophil dysfunction (Nunoi et al, 1999), and R183W, linked to developmental malformations, dystonia and deafness (Procaccio et al, 2006). Human β-actin mutations, along with those in γ-cytoplasmic actin, have been linked to Baraitser-Winter syndrome (Kemerley et al, 2017). The severity of these mutations, as well as the lack of any observed homozygous mutations in the β-actin gene, present additional evidence of its highly essential biological role.…”